Cytokine multimerization: when more is more and sometimes less

Cytokine multimerization: when more is more and sometimes less

  • Morley, J. E. & Baumgartner, R. N. Cytokine-related aging process. J. Gerontol. A 59, M924–M929 (2004).

    Article 

    Google Scholar
     

  • Symonds, M. E., Mostyn, A. & Stephenson, T. Cytokines and cytokine receptors in fetal growth and development. Biochem. Soc. Trans. 29, 33–37 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dinarello, C. A. Historical insights into cytokines. Eur. J. Immunol. 37 (Suppl. 1), S34–S45 (2007). This paper synthesizes the major milestones in cytokine biology, illustrating how discoveries of cytokines and their diverse pleiotropic functions shaped our understanding of immunity, disease mechanisms and therapeutic targeting.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hausmann, J. S. Targeting cytokines to treat autoinflammatory diseases. Clin. Immunol. 206, 23–32 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Aksentijevich, I. et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N. Engl. J. Med. 360, 2426–2437 (2009). This paper identifies and characterizes a new monogenic autoinflammatory disease (DIRA), caused by homozygous loss-of-function mutations in the IL1RN gene.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cho, S. X. et al. Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities. Nat. Commun. 11, 5794 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schroder, A. et al. IL-37 regulates allergic inflammation by counterbalancing pro-inflammatory IL-1 and IL-33. Allergy 77, 856–869 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Spencer, S. et al. Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J. Exp. Med. 216, 1986–1998 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kovarik, P., Ebner, F. & Sedlyarov, V. Posttranscriptional regulation of cytokine expression. Cytokine 89, 21–26 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, J., Qian, C. & Cao, X. Post-translational modification control of innate immunity. Immunity 45, 15–30 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Zlotnik, A. & Yoshie, O. The chemokine superfamily revisited. Immunity 36, 705–716 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hughes, C. E. & Nibbs, R. J. B. A guide to chemokines and their receptors. FEBS J. 285, 2944–2971 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cecchinato, V., Martini, V., Pirani, E., Ghovehoud, E. & Uguccioni, M. The chemokine landscape: one system multiple shades. Front. Immunol. 14, 1176619 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McFarlane, A., Pohler, E. & Moraga, I. Molecular and cellular factors determining the functional pleiotropy of cytokines. FEBS J. 290, 2525–2552 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lao, J. C. et al. Type 2 immune polarization is associated with cardiopulmonary disease in preterm infants. Sci. Transl. Med. 14, eaaz8454 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gieseck, R. L. 3rd, Wilson, M. S. & Wynn, T. A. Type 2 immunity in tissue repair and fibrosis. Nat. Rev. Immunol. 18, 62–76 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Castro, F., Cardoso, A. P., Goncalves, R. M., Serre, K. & Oliveira, M. J. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front. Immunol. 9, 847 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jones, S. A. & Jenkins, B. J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat. Rev. Immunol. 18, 773–789 (2018). This paper synthesizes advances in understanding of how the IL-6 cytokine family drives immune regulation, chronic inflammation, autoimmunity, infection and cancer, and highlights emerging therapeutic strategies targeting these cytokines to treat inflammatory diseases and malignancies.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lin, J. X. et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity 2, 331–339 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, X., Lupardus, P., Laporte, S. L. & Garcia, K. C. Structural biology of shared cytokine receptors. Annu. Rev. Immunol. 27, 29–60 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Briukhovetska, D. et al. Interleukins in cancer: from biology to therapy. Nat. Rev. Cancer 21, 481–499 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, X. et al. Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R. Structure 20, 676–687 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saxton, R. A. et al. Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10. Science 371, eabc8433 (2021). The cryo-electron microscopy structure of the IL-10 receptor complex enables fine-tuning of IL-10–IL-10Rβ affinity and cell-type-specific responses.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Banner, D. W. et al. Crystal structure of the soluble human 55 kd TNF receptor-human TNF β complex: implications for TNF receptor activation. Cell 73, 431–445 (1993). The crystal structure of the TNFβ trimer reveals key mechanistic insights into receptor assembly and signal activation.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Meller, S. et al. TH17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nat. Immunol. 16, 970–979 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hor, S. et al. The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains. J. Biol. Chem. 279, 33343–33351 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Ellisdon, A. M. et al. Homodimerization attenuates the anti-inflammatory activity of interleukin-37. Sci. Immunol. 2, eaaj1548 (2017). This paper describes the unusual functional consequences of dimerization of IL-37, namely attenuation of its bioactivity, thus identifying a structural mechanism by which the anti-inflammatory properties of this IL-1 family member can be attenuated under steady-state conditions, avoiding suppression of routine immune surveillance.

    Article 
    PubMed 

    Google Scholar
     

  • Yoon, C. et al. Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12. EMBO J. 19, 3530–3541 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lupardus, P. J. & Garcia, K. C. The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12. J. Mol. Biol. 382, 931–941 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dougan, M., Dranoff, G. & Dougan, S. K. GM-CSF, IL-3, and IL-5 family of cytokines: regulators of inflammation. Immunity 50, 796–811 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nishinakamura, R., Miyajima, A., Mee, P. J., Tybulewicz, V. L. & Murray, R. Hematopoiesis in mice lacking the entire granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 functions. Blood 88, 2458–2464 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Milburn, M. V. et al. A novel dimer configuration revealed by the crystal structure at 2.4 Å resolution of human interleukin-5. Nature 363, 172–176 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Molfino, N. A., Gossage, D., Kolbeck, R., Parker, J. M. & Geba, G. P. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin. Exp. Allergy 42, 712–737 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Roufosse, F. Targeting the interleukin-5 pathway for treatment of eosinophilic conditions other than asthma. Front. Med. 5, 49 (2018).

    Article 

    Google Scholar
     

  • Farne, H. A., Wilson, A., Powell, C., Bax, L. & Milan, S. J. Anti-IL5 therapies for asthma. Cochrane Database Syst. Rev. 9, CD010834 (2017).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dickason, R. R. & Huston, D. P. Creation of a biologically active interleukin-5 monomer. Nature 379, 652–655 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hansen, G. et al. The structure of the GM–CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 134, 496–507 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rose-John, S. Interleukin-6 family cytokines. Cold Spring Harb. Persp. Biol. 10, ea028415 (2018).

    Article 

    Google Scholar
     

  • Kang, S., Narazaki, M., Metwally, H. & Kishimoto, T. Historical overview of the interleukin-6 family cytokine. J. Exp. Med. 217, 20190347 (2020).

    Article 

    Google Scholar
     

  • Murakami, M., Kamimura, D. & Hirano, T. Pleiotropy and specificity: insights from the interleukin 6 family of cytokines. Immunity 50, 812–831 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hunter, C. A. & Jones, S. A. IL-6 as a keystone cytokine in health and disease. Nat. Immunol. 16, 448–457 (2015). This paper positions IL-6 as a central cytokine, bridging innate and adaptive immunity with broad homeostatic and pathological roles, and discusses the complexity of its signalling, highlighting how clinical experience with IL-6 antagonists informs strategic therapeutic targeting across inflammatory and immune-mediated diseases.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nagabhushanam, V. et al. Innate inhibition of adaptive immunity: mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. J. Immunol. 171, 4750–4757 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tilg, H., Trehu, E., Atkins, M. B., Dinarello, C. A. & Mier, J. W. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83, 113–118 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schett, G. Physiological effects of modulating the interleukin-6 axis. Rheumatology 57, ii43–ii50 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Si, S. & Teachey, D. T. Spotlight on tocilizumab in the treatment of CAR-T-cell-induced cytokine release syndrome: clinical evidence to date. Ther. Clin. Risk Manag. 16, 705–714 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • REMAP-CAP Investigators (Gordon, A. C. et al.) Interleukin-6 receptor antagonists in critically Ill patients with covid-19. N. Engl. J. Med. 384, 1491–1502 (2021).

  • Xu, G. Y. et al. Solution structure of recombinant human interleukin-6. J. Mol. Biol. 268, 468–481 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Boulanger, M. J., Chow, D. C., Brevnova, E. E. & Garcia, K. C. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science 300, 2101–2104 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhou, Y. et al. Structural insights into the assembly of gp130 family cytokine signaling complexes. Sci. Adv. 9, eade4395 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ward, L. D. et al. Influence of interleukin-6 (IL-6) dimerization on formation of the high affinity hexameric IL-6 receptor complex. J. Biol. Chem. 271, 20138–20144 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • May, L. T., Santhanam, U. & Sehgal, P. B. On the multimeric nature of natural human interleukin-6. J. Biol. Chem. 266, 9950–9955 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Moreno, A. et al. Interleukin-6 dimers produced by endothelial cells inhibit apoptosis of B-chronic lymphocytic leukemia cells. Blood 97, 242–249 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fong, Y. et al. Endotoxemia elicits increased circulating beta 2-IFN/IL-6 in man. J. Immunol. 142, 2321–2324 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jablons, D. M. et al. IL-6/IFN-beta-2 as a circulating hormone. Induction by cytokine administration in humans. J. Immunol. 142, 1542–1547 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Taverner, T., Hall, N. E., O’Hair, R. A. & Simpson, R. J. Characterization of an antagonist interleukin-6 dimer by stable isotope labeling, cross-linking, and mass spectrometry. J. Biol. Chem. 277, 46487–46492 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Matthews, J. M., Hammacher, A., Howlett, G. J. & Simpson, R. J. Physicochemical characterization of an antagonistic human interleukin-6 dimer. Biochemistry 37, 10671–10680 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Preuss, C. V. & Anjum, F. Tocilizumab (StatPearls, 2026).

  • Anaya, J.-M. et al. (eds) Autoimmunity: From Bench to Bedside (El Rosario Univ. Press, 2013).

  • Sabat, R. IL-10 family of cytokines. Cytokine Growth Factor Rev. 21, 315–324 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Carlini, V. et al. The multifaceted nature of IL-10: regulation, role in immunological homeostasis and its relevance to cancer, COVID-19 and post-COVID conditions. Front. Immunol. 14, 1161067 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duchmann, R., Schmitt, E., Knolle, P., Meyer zum Buschenfelde, K. H. & Neurath, M. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12. Eur. J. Immunol. 26, 934–938 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hofstetter, C., Flondor, M., Hoegl, S., Muhl, H. & Zwissler, B. Interleukin-10 aerosol reduces proinflammatory mediators in bronchoalveolar fluid of endotoxemic rat. Crit. Care Med. 33, 2317–2322 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Glocker, E. O., Kotlarz, D., Klein, C., Shah, N. & Grimbacher, B. IL-10 and IL-10 receptor defects in humans. Ann. NY Acad. Sci. 1246, 102–107 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kimball, A. B. et al. Clinical and immunologic assessment of patients with psoriasis in a randomized, double-blind, placebo-controlled trial using recombinant human interleukin 10. Arch. Dermatol. 138, 1341–1346 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brennan, F. M. Interleukin 10 and arthritis. Rheumatology 38, 293–297 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Buruiana, F. E., Sola, I. & Alonso-Coello, P. Recombinant human interleukin 10 for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev. 2010, CD005109 (2010).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Muhl, H. Pro-inflammatory signaling by IL-10 and IL-22: bad habit stirred up by interferons? Front. Immunol. 4, 18 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lauw, F. N. et al. Proinflammatory effects of IL-10 during human endotoxemia. J. Immunol. 165, 2783–2789 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Docke, W. D. et al. Comprehensive biomarker monitoring in cytokine therapy: heterogeneous, time-dependent, and persisting immune effects of interleukin-10 application in psoriasis. J. Leukoc. Biol. 85, 582–593 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Godsell, J. et al. Clinical associations of IL-10 and IL-37 in systemic lupus erythematosus. Sci. Rep. 6, 34604 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Naing, A. et al. PEGylated IL-10 (pegilodecakin) induces systemic immune activation, CD8+ T cell invigoration and polyclonal T cell expansion in cancer patients. Cancer Cell 34, 775–791.e773 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zdanov, A. et al. Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon gamma. Structure 3, 591–601 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ouyang, W., Rutz, S., Crellin, N. K., Valdez, P. A. & Hymowitz, S. G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71–109 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Josephson, K. et al. Design and analysis of an engineered human interleukin-10 monomer. J. Biol. Chem. 275, 13552–13557 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Westerhof, L. B. et al. 3D domain swapping causes extensive multimerisation of human interleukin-10 when expressed in planta. PLoS ONE 7, e46460 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gorby, C. et al. Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses. Sci. Signal. 13, eabc0653 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Knappe, A., Hor, S., Wittmann, S. & Fickenscher, H. Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri. J. Virol. 74, 3881–3887 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Larochette, V. et al. IL-26, a cytokine with roles in extracellular DNA-induced inflammation and microbial defense. Front. Immunol. 10, 204 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dang, A. T. et al. IL-26 contributes to host defense against intracellular bacteria. J. Clin. Invest. 129, 1926–1939 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Donnelly, R. P. et al. Interleukin-26: an IL-10-related cytokine produced by Th17 cells. Cytokine Growth Factor. Rev. 21, 393–401 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Corvaisier, M. et al. IL-26 is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and Th17 cell generation. PLoS Biol. 10, e1001395 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Isaacs, A. & Lindenmann, J. Virus interference. I. The interferon. Proc. R. Soc. Lond. B 147, 258–267 (1957). This paper identified interferon as a soluble factor produced by virus-infected cells that confers antiviral resistance on other cells, founding the field of interferon research and arguably the field of cytokine biology overall.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Borden, E. C. et al. Interferons at age 50: past, current and future impact on biomedicine. Nat. Rev. Drug. Discov. 6, 975–990 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xu, K. & Jin, L. The role of heparin/heparan sulphate in the IFN-gamma-led arena. Biochimie 170, 1–9 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mendoza, J. L. et al. Structure of the IFNgamma receptor complex guides design of biased agonists. Nature 567, 56–60 (2019). This paper describes how the molecular mechanism of IFNγ assembly enables the design of biased agonists.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bhat, P., Leggatt, G., Waterhouse, N. & Frazer, I. H. Interferon-gamma derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis. 8, e2836 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kak, G., Raza, M. & Tiwari, B. K. Interferon-gamma (IFN-gamma): exploring its implications in infectious diseases. Biomol. Concepts 9, 64–79 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Errante, P. R., Frazao, J. B. & Condino-Neto, A. The use of interferon-gamma therapy in chronic granulomatous disease. Recent Patents Antiinfect. Drug Discov. 3, 225–230 (2008).

    Article 
    CAS 

    Google Scholar
     

  • Yphantis, D. A. & Arakawa, T. Sedimentation equilibrium measurements of recombinant DNA derived human interferon gamma. Biochemistry 26, 5422–5427 (1987).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Walter, M. R. et al. Crystal structure of a complex between interferon-gamma and its soluble high-affinity receptor. Nature 376, 230–235 (1995). Breakthrough crystal structure demonstrating how IFNγ dimer formation enables receptor engagement.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lelios, I. et al. Emerging roles of IL-34 in health and disease. J. Exp. Med. 217, 20190290 (2020).

    Article 

    Google Scholar
     

  • Xie, X. et al. TREM2 acts as a receptor for IL-34 to suppress acute myeloid leukemia in mice. Blood 141, 3184–3198 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Greter, M. et al. Stroma-derived interleukin-34 controls the development and maintenance of Langerhans cells and the maintenance of microglia. Immunity 37, 1050–1060 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bezie, S. et al. IL-34 is a Treg-specific cytokine and mediates transplant tolerance. J. Clin. Invest. 125, 3952–3964 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Garceau, V. et al. Pivotal advance: avian colony-stimulating factor 1 (CSF-1), interleukin-34 (IL-34), and CSF-1 receptor genes and gene products. J. Leukoc. Biol. 87, 753–764 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Baghdadi, M. et al. Interleukin-34, a comprehensive review. J. Leukoc. Biol. 104, 931–951 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nandi, S. et al. The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Dev. Biol. 367, 100–113 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ushach, I. & Zlotnik, A. Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage. J. Leukoc. Biol. 100, 481–489 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dai, X. M., Zong, X. H., Sylvestre, V. & Stanley, E. R. Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1. Blood 103, 1114–1123 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jeannin, P., Paolini, L., Adam, C. & Delneste, Y. The roles of CSFs on the functional polarization of tumor-associated macrophages. FEBS J. 285, 680–699 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chitu, V., Gokhan, S., Nandi, S., Mehler, M. F. & Stanley, E. R. Emerging roles for CSF-1 receptor and its ligands in the nervous system. Trends Neurosci. 39, 378–393 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dai, X. M. et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99, 111–120 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hamilton, J. A., Cook, A. D. & Tak, P. P. Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. Nat. Rev. Drug Discov. 16, 53–70 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Benner, B. et al. Pexidartinib, a novel small molecule CSF-1R inhibitor in use for tenosynovial giant cell tumor: a systematic review of pre-clinical and clinical development. Drug. Design Dev. Ther. 14, 1693–1704 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Liu, H. et al. The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1. Biochim. Biophys. Acta 1824, 938–945 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Garlanda, C., Dinarello, C. A. & Mantovani, A. The interleukin-1 family: back to the future. Immunity 39, 1003–1018 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nold, M. F. et al. IL-37 is a fundamental inhibitor of innate immunity. Nat. Immunol. 11, 1014–1022 (2010). This is the first study functionally characterizing IL-37 (formerly known as IL-1 family member 7) as a broad-acting anti-inflammatory IL-1 family member.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nold-Petry, C. A. et al. IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat. Immunol. 16, 354–365 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rudloff, I. et al. Brief report: interleukin-38 exerts antiinflammatory functions and is associated with disease activity in systemic lupus erythematosus. Arthritis Rheumatol. 67, 3219–3225 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • van de Veerdonk, F. L. et al. IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist. Proc. Natl Acad. Sci. 109, 3001–3005 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nold-Petry, C. A. & Nold, M. F. Rationale for IL-37 as a novel therapeutic agent in inflammation. Expert. Rev. Clin. Immunol. 18, 1203–1206 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ballak, D. B. et al. IL-37 protects against obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 4711 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cho, S. X., Rudloff, I., Ellisdon, A. M., Nold-Petry, C. A. & Nold, M. F. Thirteen years to get from b to a: one of the neglected isoforms of IL-37 enters the stage. Cell Mol. Immunol. 21, 201–202 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhao, M. et al. IL-37 isoform D downregulates pro-inflammatory cytokines expression in a Smad3-dependent manner. Cell Death Dis. 9, 582 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wei, R. et al. The nuclear cytokine IL-37a controls lethal cytokine storms primarily via IL-1R8-independent transcriptional upregulation of PPARɣ. Cell Mol. Immunol. 20, 1428–1444 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sharma, S. et al. The IL-1 family member 7b translocates to the nucleus and down-regulates proinflammatory cytokines. J. Immunol. 180, 5477–5482 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rudloff, I. et al. Parsing the IL-37-mediated suppression of inflammasome function. Cells 9, 178 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rudloff, I. et al. Monocytes and dendritic cells are the primary sources of interleukin 37 in human immune cells. J. Leukoc. Biol. 101, 901–911 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bujotzek, A. et al. Protein engineering of a stable and potent anti-inflammatory IL-37-Fc fusion with enhanced therapeutic potential. Cell Chem. Biol. 29, 586–596.e584 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bodmer, J. L., Schneider, P. & Tschopp, J. The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat. Rev. Cancer 2, 420–430 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Locksley, R. M., Killeen, N. & Lenardo, M. J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Summers deLuca, L. & Gommerman, J. L. Fine-tuning of dendritic cell biology by the TNF superfamily. Nat. Rev. Immunol. 12, 339–351 (2012).

    Article 
    PubMed 

    Google Scholar
     

  • Paul, S. & Lal, G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front. Immunol. 8, 1124 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Smulski, C. R. & Eibel, H. BAFF and BAFF-receptor in B cell selection and survival. Front. Immunol. 9, 2285 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Legler, K. et al. The novel TRAIL-receptor agonist APG350 exerts superior therapeutic activity in pancreatic cancer cells. Cell Death Dis. 9, 445 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Grimstad, O. Tumor necrosis factor and the tenacious alpha. JAMA Dermatol. 152, 557 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Clark, I. A. How TNF was recognized as a key mechanism of disease. Cytokine Growth Factor Rev. 18, 335–343 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vandenabeele, P., Declercq, W., Beyaert, R. & Fiers, W. Two tumour necrosis factor receptors: structure and function. Trends Cell Biol. 5, 392–399 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Porteu, F. & Nathan, C. Shedding of tumor necrosis factor receptors by activated human neutrophils. J. Exp. Med. 172, 599–607 (1990).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Grell, M. et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83, 793–802 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, X. & Lin, Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol. Sin. 29, 1275–1288 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Medler, J. & Wajant, H. Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target. Expert Opin. Ther. Targets 23, 295–307 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jang, D. I. et al. The role of tumor necrosis factor α (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics. Int. J. Mol. Sci. 22, 22052719 (2021).

    Article 

    Google Scholar
     

  • Dinarello, C. A. et al. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J. Exp. Med. 163, 1433–1450 (1986).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Monaco, C., Nanchahal, J., Taylor, P. & Feldmann, M. Anti-TNF therapy: past, present and future. Int. Immunol. 27, 55–62 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kucka, K. & Wajant, H. Receptor oligomerization and its relevance for signaling by receptors of the tumor necrosis factor receptor superfamily. Front. Cell Dev. Biol. 8, 615141 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Eck, M. J. & Sprang, S. R. The structure of tumor necrosis factor-α at 2.6 Å resolution. Implications for receptor binding. J. Biol. Chem. 264, 17595–17605 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vanamee, E. S. & Faustman, D. L. The benefits of clustering in TNF receptor superfamily signaling. Front. Immunol. 14, 1225704 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lim, C. S., Lee, J., Kim, J. W. & Lee, J. O. Highly ordered clustering of TNFα and BAFF ligand–receptor–intracellular adaptor complexes on a lipid membrane. Nat. Commun. 16, 5551 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K. & Flavell, R. A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24, 99–146 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Annes, J. P., Munger, J. S. & Rifkin, D. B. Making sense of latent TGFβ activation. J. Cell Sci. 116, 217–224 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Khalil, N. TGF-β: from latent to active. Microbes Infect. 1, 1255–1263 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Travis, M. A. & Sheppard, D. TGF-β activation and function in immunity. Annu. Rev. Immunol. 32, 51–82 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kulkarni, A. B. et al. Transforming growth factor β 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl Acad. Sci. 90, 770–774 (1993). This paper shows that TGFβ1 deficiency causes lethal systemic inflammation in mice, establishing TGFβ as an essential immune suppressor and master regulator of immune homeostasis.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, M. O. & Flavell, R. A. TGF-beta: a master of all T. Cell Trades Cell 134, 392–404 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, W. & Ten Dijke, P. Immunoregulation by members of the TGFβ superfamily. Nat. Rev. Immunol. 16, 723–740 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Thorbecke, G. J. et al. Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. Proc. Natl Acad. Sci. 89, 7375–7379 (1992).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Raz, E. et al. Modulation of disease activity in murine systemic lupus erythematosus by cytokine gene delivery. Lupus 4, 286–292 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Margadant, C. & Sonnenberg, A. Integrin-TGF-β crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 11, 97–105 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Walton, K. L., Johnson, K. E. & Harrison, C. A. Targeting TGF-β mediated SMAD signaling for the prevention of fibrosis. Front. Pharmacol. 8, 461 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Neuzillet, C. et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther. 147, 22–31 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Padua, D. & Massague, J. Roles of TGFβ in metastasis. Cell Res. 19, 89–102 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Teixeira, A. F., Ten Dijke, P. & Zhu, H. J. On-target anti-TGF-β therapies are not succeeding in clinical cancer treatments: what are remaining challenges? Front. Cell Dev. Biol. 8, 605 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, B. G., Malek, E., Choi, S. H., Ignatz-Hoover, J. J. & Driscoll, J. J. Novel therapies emerging in oncology to target the TGF-β pathway. J. Hematol. Oncol. 14, 55 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ge, R. & Huang, G. M. Targeting transforming growth factor beta signaling in metastatic osteosarcoma. J. Bone Oncol. 43, 100513 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mittl, P. R. et al. The crystal structure of TGF-β 3 and comparison to TGF-β 2: implications for receptor binding. Protein Sci. 5, 1261–1271 (1996).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Groppe, J. et al. Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol. Cell 29, 157–168 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Radaev, S. et al. Ternary complex of transforming growth factor-β1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily. J. Biol. Chem. 285, 14806–14814 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, S. K. et al. An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling. J. Biol. Chem. 292, 7173–7188 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vignali, D. A. & Kuchroo, V. K. IL-12 family cytokines: immunological playmakers. Nat. Immunol. 13, 722–728 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Teng, M. W. et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 21, 719–729 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006). This paper establishes that TGFβ in combination with pro-inflammatory cytokines drives TH17 cell differentiation, whereas together with IL-2, TGFβ promotes Treg cell differentiation, thus defining reciprocal TH17–Treg cell fates.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kastelein, R. A., Hunter, C. A. & Cua, D. J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, X. et al. Interleukin (IL)-39 [IL-23p19/Epstein–Barr virus-induced 3 (Ebi3)] induces differentiation/expansion of neutrophils in lupus-prone mice. Clin. Exp. Immunol. 186, 144–156 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stumhofer, J. S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Presky, D. H. et al. A functional interleukin 12 receptor complex is composed of two β-type cytokine receptor subunits. Proc. Natl Acad. Sci. 93, 14002–14007 (1996).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zheng, H., Ban, Y., Wei, F. & Ma, X. Regulation of interleukin-12 production in antigen-presenting cells. Adv. Exp. Med. Biol. 941, 117–138 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • el-Shabrawi, Y., Livir-Rallatos, C., Christen, W., Baltatzis, S. & Foster, C. S. High levels of interleukin-12 in the aqueous humor and vitreous of patients with uveitis. Ophthalmology 105, 1659–1663 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pope, R. M. & Shahrara, S. Possible roles of IL-12-family cytokines in rheumatoid arthritis. Nat. Rev. Rheumatol. 9, 252–256 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Balashov, K. E., Smith, D. R., Khoury, S. J., Hafler, D. A. & Weiner, H. L. Increased interleukin 12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand. Proc. Natl Acad. Sci. 94, 599–603 (1997).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Comabella, M. et al. Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J. Clin. Invest. 102, 671–678 (1998).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bright, J. J., Famakin, B. M., Du, C. & Sriram, S. Expression of IL-12 in CNS and lymphoid organs of mice with experimental allergic encephalitis. J. Neuroimmunol. 82, 22–30 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003). This paper revealed that IL-23, not IL-12, is essential for driving autoimmune neuroinflammation in experimental models.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Khader, S. A. & Thirunavukkarasu, S. The tale of IL-12 and IL-23: a paradigm shift. J. Immunol. 202, 629–630 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Glassman, C. R. et al. Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells. Cell 184, 983–999.e924 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bloch, Y. et al. Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23. Nat. Struct. Mol. Biol. 31, 591–597 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ling, P. et al. Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. J. Immunol. 154, 116–127 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, Y., Wang, H., Lu, H. & Hua, S. Regulation of memory T cells by interleukin-23. Int. Arch. Allergy Immunol. 169, 157–162 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bastos, K. R. et al. What kind of message does IL-12/IL-23 bring to macrophages and dendritic cells. Microbes Infect. 6, 630–636 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Razawy, W., van Driel, M. & Lubberts, E. The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis and bone remodeling. Eur. J. Immunol. 48, 220–229 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Neurath, M. F. IL-23 in inflammatory bowel diseases and colon cancer. Cytokine Growth Factor. Rev. 45, 1–8 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Savage, L. J., Wittmann, M., McGonagle, D. & Helliwell, P. S. Ustekinumab in the treatment of psoriasis and psoriatic arthritis. Rheumatol. Ther. 2, 1–16 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Benson, J. M. et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. mAbs 3, 535–545 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kashani, A. & Schwartz, D. A. The expanding role of anti-IL-12 and/or anti-IL-23 antibodies in the treatment of inflammatory bowel disease. Gastroenterol. Hepatol. 15, 255–265 (2019).


    Google Scholar
     

  • Pflanz, S. et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 172, 2225–2231 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kourko, O., Seaver, K., Odoardi, N., Basta, S. & Gee, K. IL-27, IL-30, and IL-35: a cytokine triumvirate in cancer. Front. Oncol. 9, 969 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Villarino, A. V. & Hunter, C. A. Biology of recently discovered cytokines: discerning the pro- and anti-inflammatory properties of interleukin-27. Arthritis Res. Ther. 6, 225–233 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moro, K. et al. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat. Immunol. 17, 76–86 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Awasthi, A. et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 8, 1380–1389 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kimura, D. et al. Interleukin-27-producing CD4+ T cells regulate protective immunity during malaria parasite infection. Immunity 44, 672–682 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jones, G. W., Hill, D. G., Cardus, A. & Jones, S. A. IL-27: a double agent in the IL-6 family. Clin. Exp. Immunol. 193, 37–46 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bosmann, M. & Ward, P. A. Modulation of inflammation by interleukin-27. J. Leukoc. Biol. 94, 1159–1165 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stumhofer, J. S. et al. A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nat. Immunol. 11, 1119–1126 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002). This paper describes IL-27 as a heterodimeric cytokine composed of p28 and EBI3.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Caveney, N. A., Glassman, C. R., Jude, K. M., Tsutsumi, N. & Garcia, K. C. Structure of the IL-27 quaternary receptor signaling complex. eLife 11, e78463 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jin, Y. et al. Structural insights into the assembly and activation of the IL-27 signaling complex. EMBO Rep. 23, e55450 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bello, R. O. et al. The role, involvement and function(s) of interleukin-35 and interleukin-37 in disease pathogenesis. Int. J. Mol. Sci. 19, 19041149 (2018).

    Article 

    Google Scholar
     

  • Zhang, J. et al. Interleukin-35 in immune-related diseases: protection or destruction. Immunology 157, 13–20 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Devergne, O., Birkenbach, M. & Kieff, E. Epstein–Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proc. Natl Acad. Sci. 94, 12041–12046 (1997).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Collison, L. W. et al. The composition and signaling of the IL-35 receptor are unconventional. Nat. Immunol. 13, 290–299 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Floss, D. M. et al. IL-6/IL-12 cytokine receptor shuffling of extra- and intracellular domains reveals canonical STAT activation via synthetic IL-35 and IL-39 signaling. Sci. Rep. 7, 15172 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, X. et al. A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in lupus-like mice. Eur. J. Immunol. 46, 1343–1350 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, X. et al. Anti-IL-39 (IL-23p19/Ebi3) polyclonal antibodies ameliorate autoimmune symptoms in lupus-like mice. Mol. Med. Rep. 17, 1660–1666 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • Garbers, C. et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 23, 85–97 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McGeachy, M. J., Cua, D. J. & Gaffen, S. L. The IL-17 family of cytokines in health and disease. Immunity 50, 892–906 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gaffen, S. L. Structure and signalling in the IL-17 receptor family. Nat. Rev. Immunol. 9, 556–567 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rouvier, E., Luciani, M. F., Mattei, M. G., Denizot, F. & Golstein, P. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J. Immunol. 150, 5445–5456 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005). This paper discovered a distinct lineage of CD4 T cells regulating tissue inflammation that expresses IL-17, thus expanding the T helper paradigm by a third polarization.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Monin, L. & Gaffen, S. L. Interleukin 17 family cytokines: signaling mechanisms, biological activities, and therapeutic implications. Cold Spring Harb. Persp. Biol. 10, a028522 (2018). This paper integrates current knowledge of the IL-17 cytokine family’s unique signalling mechanisms, diverse biological activities in host defence and inflammation, and emerging therapeutic implications, highlighting both protective and pathogenic roles of IL-17 family members and the rationale for targeting them in chronic inflammatory diseases.

    Article 

    Google Scholar
     

  • Zwicky, P., Unger, S. & Becher, B. Targeting interleukin-17 in chronic inflammatory disease: a clinical perspective. J. Exp. Med. 217, 20191123 (2020).

    Article 

    Google Scholar
     

  • van der Fits, L. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Langley, R. G. et al. Secukinumab in plaque psoriasis — results of two phase 3 trials. N. Engl. J. Med. 371, 326–338 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Shi, Y. et al. A novel cytokine receptor–ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity. J. Biol. Chem. 275, 19167–19176 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Reynolds, J. M. et al. Interleukin-17B antagonizes interleukin-25-mediated mucosal inflammation. Immunity 42, 692–703 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ramirez-Carrozzi, V. et al. IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat. Immunol. 12, 1159–1166 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, J. et al. Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93. Immunity 54, 673–686 e674 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saddawi-Konefka, R. et al. Nrf2 induces IL-17D to mediate tumor and virus surveillance. Cell Rep. 16, 2348–2358 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, J. et al. IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J. Biol. Chem. 276, 1660–1664 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pan, G. et al. Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice. J. Immunol. 167, 6559–6567 (2001). Together with Fallon etal. (2006), this paper describes the role of IL-25 and the innate lymphoid cell ILC2 in type-2-polarized inflammation, contributing to the rationale for targeting the relevant signalling cascade, which also involves IL-33 and TSLP, in asthma and allergy.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fallon, P. G. et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wright, J. F. et al. Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J. Biol. Chem. 282, 13447–13455 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Goepfert, A., Lehmann, S., Wirth, E. & Rondeau, J. M. The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties. Sci. Rep. 7, 8906 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goepfert, A., Lehmann, S., Blank, J., Kolbinger, F. & Rondeau, J. M. Structural analysis reveals that the cytokine IL-17F forms a homodimeric complex with receptor IL-17RC to drive IL-17RA-independent signaling. Immunity 52, 499–512.e495 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wilson, S. C. et al. Organizing structural principles of the IL-17 ligand-receptor axis. Nature 609, 622–629 (2022). This paper provides several structural insights into how IL-17 family homodimer and heterodimer formation supports receptor assembly and downstream signalling.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leonard, W. J., Lin, J. X. & O’Shea, J. J. The γc family of cytokines: basic biology to therapeutic ramifications. Immunity 50, 832–850 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wrenshall, L. E. et al. Identification of a cytotoxic form of dimeric interleukin-2 in murine tissues. PLoS ONE 9, e102191 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gounni, A. S. & Koussih, L. SUMO wrestling in the airway epithelium: does it regulate thymic stromal lymphopoietin? Am. J. Resp. Cell Mol. Biol. 66, 591–592 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Verstraete, K. et al. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat. Commun. 8, 14937 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McDonald, N. Q., Panayotatos, N. & Hendrickson, W. A. Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing. EMBO J. 14, 2689–2699 (1995).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rudloff, I., Bachmann, M., Pfeilschifter, J. & Muhl, H. Mechanisms of rapid induction of interleukin-22 in activated T cells and its modulation by cyclosporin A. J. Biol. Chem. 287, 4531–4543 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Muhl, H. et al. IL-22 in tissue-protective therapy. Br. J. Pharmacol. 169, 761–771 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Boniface, K. et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin. Exp. Immunol. 150, 407–415 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ikeuchi, H. et al. Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 52, 1037–1046 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saxton, R. A. et al. The tissue protective functions of interleukin-22 can be decoupled from pro-inflammatory actions through structure-based design. Immunity 54, 660–672.e669 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jones, B. C., Logsdon, N. J. & Walter, M. R. Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure 16, 1333–1344 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de Oliveira Neto, M. et al. Interleukin-22 forms dimers that are recognized by two interleukin-22R1 receptor chains. Biophys. J. 94, 1754–1765 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nagem, R. A. et al. Crystal structure of recombinant human interleukin-22. Structure 10, 1051–1062 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Radhakrishnan, R. et al. Zinc mediated dimer of human interferon-alpha 2b revealed by X-ray crystallography. Structure 4, 1453–1463 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Karpusas, M. et al. The crystal structure of human interferon beta at 2.2-A resolution. Proc. Natl Acad. Sci. 94, 11813–11818 (1997).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thomas, C. et al. Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell 146, 621–632 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dellgren, C., Gad, H. H., Hamming, O. J., Melchjorsen, J. & Hartmann, R. Human interferon-λ3 is a potent member of the type III interferon family. Genes. Immun. 10, 125–131 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Herrington-Symes, A., Choi, J. W. & Brocchini, S. Interferon dimers: IFN-PEG-IFN. J. Drug Target. 25, 881–890 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chang, C. H. et al. A new method to produce monoPEGylated dimeric cytokines shown with human interferon-α2b. Bioconjug Chem. 20, 1899–1907 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dinarello, C. A., Simon, A. & van der Meer, J. W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 11, 633–652 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cavalli, G. & Dinarello, C. A. Anakinra therapy for non-cancer inflammatory diseases. Front. Pharmacol. 9, 1157 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bui, C. B. et al. Interleukin-1 receptor antagonist protects newborn mice against pulmonary hypertension. Front. Immunol. 10, 1480 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nold, M. F. et al. Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia. Proc. Natl Acad. Sci. 110, 14384–14389 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rudloff, I. et al. Refining anti-inflammatory therapy strategies for bronchopulmonary dysplasia. J. Cell Mol. Med. 21, 1128–1138 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chang, B. S. et al. Formation of an active dimer during storage of interleukin-1 receptor antagonist in aqueous solution. Biophys. J. 71, 3399–3406 (1996).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, C. et al. IL-16 signaling specifically induces STAT6 activation through CD4. Cytokine 38, 145–150 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hall, G. et al. Structure of a potential therapeutic antibody bound to interleukin-16 (IL-16): mechanistic insights and new therapeutic opportunities. J. Biol. Chem. 291, 16840–16848 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Center, D. M., Kornfeld, H. & Cruikshank, W. W. Interleukin 16 and its function as a CD4 ligand. Immunol. Today 17, 476–481 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Deckers, J. et al. Engineering cytokine therapeutics. Nat. Rev. Bioeng. 1, 286–303 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, X., Rickert, M. & Garcia, K. C. Structure of the quaternary complex of interleukin-2 with its β, α, and ɣc receptors. Science 310, 1159–1163 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Corren, J. & Ziegler, S. F. TSLP: from allergy to cancer. Nat. Immunol. 20, 1603–1609 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yan, J., Smyth, M. J. & Teng, M. W. L. Interleukin (IL)-12 and IL-23 and their conflicting roles in cancer. Cold Spring Harb. Persp. Biol. 10, ea028530 (2018).

    Article 

    Google Scholar
     

  • Dambuza, I. M. et al. IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease. Nat. Commun. 8, 719 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ramnath, D. et al. TLR3 drives IRF6-dependent IL-23p19 expression and p19/EBI3 heterodimer formation in keratinocytes. Immunol. Cell Biol. 93, 771–779 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Walter, M. R. & Nagabhushan, T. L. Crystal structure of interleukin 10 reveals an interferon gamma-like fold. Biochemistry 34, 12118–12125 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rudloff, I. et al. Molecular signature of interleukin-22 in colon carcinoma cells and organoid models. Transl. Res. 216, 1–22 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Hernandez, P., Gronke, K. & Diefenbach, A. A catch-22: interleukin-22 and cancer. Eur. J. Immunol. 48, 15–31 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Poli, C. et al. IL-26 confers proinflammatory properties to extracellular DNA. J. Immunol. 198, 3650–3661 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Parker, B. S., Rautela, J. & Hertzog, P. J. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer 16, 131–144 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Mendoza, J. L. et al. The IFN-λ–IFN-λR1–IL-10Rβ complex reveals structural features underlying type III IFN functional plasticity. Immunity 46, 379–392 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cersosimo, F. et al. CSF-1R in cancer: more than a myeloid cell receptor. Cancers 16, 282 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, A. Y., Wolchok, J. D. & Bass, A. R. TNF in the era of immune checkpoint inhibitors: friend or foe? Nat. Rev. Rheumatol. 17, 213–223 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chung, C. W., Cooke, R. M., Proudfoot, A. E. & Wells, T. N. The three-dimensional solution structure of RANTES. Biochemistry 34, 9307–9314 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Proudfoot, A. E. et al. Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc. Natl Acad. Sci. 100, 1885–1890 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, K. et al. Structural basis of CXC chemokine receptor 2 activation and signalling. Nature 585, 135–140 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ishimoto, N. et al. Structural basis of CXC chemokine receptor 1 ligand binding and activation. Nat. Commun. 14, 4107 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bakouny, Z. & Choueiri, T. K. IL-8 and cancer prognosis on immunotherapy. Nat. Med. 26, 650–651 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ostuni, M. A. et al. CX3CL1 homo-oligomerization drives cell-to-cell adherence. Sci. Rep. 10, 9069 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tuinstra, R. L. et al. Interconversion between two unrelated protein folds in the lymphotactin native state. Proc. Natl Acad. Sci. 105, 5057–5062 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wright, J. F. et al. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J. Immunol. 181, 2799–2805 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huangfu, L., Li, R., Huang, Y. & Wang, S. The IL-17 family in diseases: from bench to bedside. Signal Transduct. Target. Ther. 8, 402 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goebel, E. J., Hart, K. N., McCoy, J. C. & Thompson, T. B. Structural biology of the TGFβ family. Exp. Biol. Med. 244, 1530–1546 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Gaballa, J. M. et al. International nomenclature guidelines for the IL-1 family of cytokines and receptors. Nat. Immunol. 25, 581–582 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Eisenmesser, E. Z. et al. Interleukin-37 monomer is the active form for reducing innate immunity. Proc. Natl Acad. Sci. 116, 5514–5522 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar