Morley, J. E. & Baumgartner, R. N. Cytokine-related aging process. J. Gerontol. A 59, M924–M929 (2004).
Symonds, M. E., Mostyn, A. & Stephenson, T. Cytokines and cytokine receptors in fetal growth and development. Biochem. Soc. Trans. 29, 33–37 (2001).
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.
Hausmann, J. S. Targeting cytokines to treat autoinflammatory diseases. Clin. Immunol. 206, 23–32 (2019).
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.
Cho, S. X. et al. Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities. Nat. Commun. 11, 5794 (2020).
Schroder, A. et al. IL-37 regulates allergic inflammation by counterbalancing pro-inflammatory IL-1 and IL-33. Allergy 77, 856–869 (2022).
Spencer, S. et al. Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J. Exp. Med. 216, 1986–1998 (2019).
Kovarik, P., Ebner, F. & Sedlyarov, V. Posttranscriptional regulation of cytokine expression. Cytokine 89, 21–26 (2017).
Liu, J., Qian, C. & Cao, X. Post-translational modification control of innate immunity. Immunity 45, 15–30 (2016).
Zlotnik, A. & Yoshie, O. The chemokine superfamily revisited. Immunity 36, 705–716 (2012).
Hughes, C. E. & Nibbs, R. J. B. A guide to chemokines and their receptors. FEBS J. 285, 2944–2971 (2018).
Cecchinato, V., Martini, V., Pirani, E., Ghovehoud, E. & Uguccioni, M. The chemokine landscape: one system multiple shades. Front. Immunol. 14, 1176619 (2023).
McFarlane, A., Pohler, E. & Moraga, I. Molecular and cellular factors determining the functional pleiotropy of cytokines. FEBS J. 290, 2525–2552 (2023).
Lao, J. C. et al. Type 2 immune polarization is associated with cardiopulmonary disease in preterm infants. Sci. Transl. Med. 14, eaaz8454 (2022).
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).
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).
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.
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).
Wang, X., Lupardus, P., Laporte, S. L. & Garcia, K. C. Structural biology of shared cytokine receptors. Annu. Rev. Immunol. 27, 29–60 (2009).
Briukhovetska, D. et al. Interleukins in cancer: from biology to therapy. Nat. Rev. Cancer 21, 481–499 (2021).
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).
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.
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.
Meller, S. et al. TH17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nat. Immunol. 16, 970–979 (2015).
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).
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.
Yoon, C. et al. Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12. EMBO J. 19, 3530–3541 (2000).
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).
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).
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).
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).
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).
Roufosse, F. Targeting the interleukin-5 pathway for treatment of eosinophilic conditions other than asthma. Front. Med. 5, 49 (2018).
Farne, H. A., Wilson, A., Powell, C., Bax, L. & Milan, S. J. Anti-IL5 therapies for asthma. Cochrane Database Syst. Rev. 9, CD010834 (2017).
Dickason, R. R. & Huston, D. P. Creation of a biologically active interleukin-5 monomer. Nature 379, 652–655 (1996).
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).
Rose-John, S. Interleukin-6 family cytokines. Cold Spring Harb. Persp. Biol. 10, ea028415 (2018).
Kang, S., Narazaki, M., Metwally, H. & Kishimoto, T. Historical overview of the interleukin-6 family cytokine. J. Exp. Med. 217, 20190347 (2020).
Murakami, M., Kamimura, D. & Hirano, T. Pleiotropy and specificity: insights from the interleukin 6 family of cytokines. Immunity 50, 812–831 (2019).
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.
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).
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).
Schett, G. Physiological effects of modulating the interleukin-6 axis. Rheumatology 57, ii43–ii50 (2018).
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).
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).
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).
Zhou, Y. et al. Structural insights into the assembly of gp130 family cytokine signaling complexes. Sci. Adv. 9, eade4395 (2023).
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).
May, L. T., Santhanam, U. & Sehgal, P. B. On the multimeric nature of natural human interleukin-6. J. Biol. Chem. 266, 9950–9955 (1991).
Moreno, A. et al. Interleukin-6 dimers produced by endothelial cells inhibit apoptosis of B-chronic lymphocytic leukemia cells. Blood 97, 242–249 (2001).
Fong, Y. et al. Endotoxemia elicits increased circulating beta 2-IFN/IL-6 in man. J. Immunol. 142, 2321–2324 (1989).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Brennan, F. M. Interleukin 10 and arthritis. Rheumatology 38, 293–297 (1999).
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).
Muhl, H. Pro-inflammatory signaling by IL-10 and IL-22: bad habit stirred up by interferons? Front. Immunol. 4, 18 (2013).
Lauw, F. N. et al. Proinflammatory effects of IL-10 during human endotoxemia. J. Immunol. 165, 2783–2789 (2000).
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).
Godsell, J. et al. Clinical associations of IL-10 and IL-37 in systemic lupus erythematosus. Sci. Rep. 6, 34604 (2016).
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).
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).
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).
Josephson, K. et al. Design and analysis of an engineered human interleukin-10 monomer. J. Biol. Chem. 275, 13552–13557 (2000).
Westerhof, L. B. et al. 3D domain swapping causes extensive multimerisation of human interleukin-10 when expressed in planta. PLoS ONE 7, e46460 (2012).
Gorby, C. et al. Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses. Sci. Signal. 13, eabc0653 (2020).
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).
Larochette, V. et al. IL-26, a cytokine with roles in extracellular DNA-induced inflammation and microbial defense. Front. Immunol. 10, 204 (2019).
Dang, A. T. et al. IL-26 contributes to host defense against intracellular bacteria. J. Clin. Invest. 129, 1926–1939 (2019).
Donnelly, R. P. et al. Interleukin-26: an IL-10-related cytokine produced by Th17 cells. Cytokine Growth Factor. Rev. 21, 393–401 (2010).
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).
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.
Borden, E. C. et al. Interferons at age 50: past, current and future impact on biomedicine. Nat. Rev. Drug. Discov. 6, 975–990 (2007).
Xu, K. & Jin, L. The role of heparin/heparan sulphate in the IFN-gamma-led arena. Biochimie 170, 1–9 (2020).
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.
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).
Kak, G., Raza, M. & Tiwari, B. K. Interferon-gamma (IFN-gamma): exploring its implications in infectious diseases. Biomol. Concepts 9, 64–79 (2018).
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).
Yphantis, D. A. & Arakawa, T. Sedimentation equilibrium measurements of recombinant DNA derived human interferon gamma. Biochemistry 26, 5422–5427 (1987).
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.
Lelios, I. et al. Emerging roles of IL-34 in health and disease. J. Exp. Med. 217, 20190290 (2020).
Xie, X. et al. TREM2 acts as a receptor for IL-34 to suppress acute myeloid leukemia in mice. Blood 141, 3184–3198 (2023).
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).
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).
Bezie, S. et al. IL-34 is a Treg-specific cytokine and mediates transplant tolerance. J. Clin. Invest. 125, 3952–3964 (2015).
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).
Baghdadi, M. et al. Interleukin-34, a comprehensive review. J. Leukoc. Biol. 104, 931–951 (2018).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Garlanda, C., Dinarello, C. A. & Mantovani, A. The interleukin-1 family: back to the future. Immunity 39, 1003–1018 (2013).
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.
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).
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).
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).
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).
Ballak, D. B. et al. IL-37 protects against obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 4711 (2014).
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).
Zhao, M. et al. IL-37 isoform D downregulates pro-inflammatory cytokines expression in a Smad3-dependent manner. Cell Death Dis. 9, 582 (2018).
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).
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).
Rudloff, I. et al. Parsing the IL-37-mediated suppression of inflammasome function. Cells 9, 178 (2020).
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).
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).
Bodmer, J. L., Schneider, P. & Tschopp, J. The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26 (2002).
Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat. Rev. Cancer 2, 420–430 (2002).
Locksley, R. M., Killeen, N. & Lenardo, M. J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501 (2001).
Summers deLuca, L. & Gommerman, J. L. Fine-tuning of dendritic cell biology by the TNF superfamily. Nat. Rev. Immunol. 12, 339–351 (2012).
Paul, S. & Lal, G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front. Immunol. 8, 1124 (2017).
Smulski, C. R. & Eibel, H. BAFF and BAFF-receptor in B cell selection and survival. Front. Immunol. 9, 2285 (2018).
Legler, K. et al. The novel TRAIL-receptor agonist APG350 exerts superior therapeutic activity in pancreatic cancer cells. Cell Death Dis. 9, 445 (2018).
Grimstad, O. Tumor necrosis factor and the tenacious alpha. JAMA Dermatol. 152, 557 (2016).
Clark, I. A. How TNF was recognized as a key mechanism of disease. Cytokine Growth Factor Rev. 18, 335–343 (2007).
Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).
Vandenabeele, P., Declercq, W., Beyaert, R. & Fiers, W. Two tumour necrosis factor receptors: structure and function. Trends Cell Biol. 5, 392–399 (1995).
Porteu, F. & Nathan, C. Shedding of tumor necrosis factor receptors by activated human neutrophils. J. Exp. Med. 172, 599–607 (1990).
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).
Wang, X. & Lin, Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol. Sin. 29, 1275–1288 (2008).
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).
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).
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).
Monaco, C., Nanchahal, J., Taylor, P. & Feldmann, M. Anti-TNF therapy: past, present and future. Int. Immunol. 27, 55–62 (2015).
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).
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).
Vanamee, E. S. & Faustman, D. L. The benefits of clustering in TNF receptor superfamily signaling. Front. Immunol. 14, 1225704 (2023).
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).
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).
Annes, J. P., Munger, J. S. & Rifkin, D. B. Making sense of latent TGFβ activation. J. Cell Sci. 116, 217–224 (2003).
Khalil, N. TGF-β: from latent to active. Microbes Infect. 1, 1255–1263 (1999).
Travis, M. A. & Sheppard, D. TGF-β activation and function in immunity. Annu. Rev. Immunol. 32, 51–82 (2014).
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.
Li, M. O. & Flavell, R. A. TGF-beta: a master of all T. Cell Trades Cell 134, 392–404 (2008).
Chen, W. & Ten Dijke, P. Immunoregulation by members of the TGFβ superfamily. Nat. Rev. Immunol. 16, 723–740 (2016).
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).
Raz, E. et al. Modulation of disease activity in murine systemic lupus erythematosus by cytokine gene delivery. Lupus 4, 286–292 (1995).
Margadant, C. & Sonnenberg, A. Integrin-TGF-β crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 11, 97–105 (2010).
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).
Neuzillet, C. et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther. 147, 22–31 (2015).
Padua, D. & Massague, J. Roles of TGFβ in metastasis. Cell Res. 19, 89–102 (2009).
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).
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).
Ge, R. & Huang, G. M. Targeting transforming growth factor beta signaling in metastatic osteosarcoma. J. Bone Oncol. 43, 100513 (2023).
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).
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).
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).
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).
Vignali, D. A. & Kuchroo, V. K. IL-12 family cytokines: immunological playmakers. Nat. Immunol. 13, 722–728 (2012).
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).
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.
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).
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).
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).
Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).
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).
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).
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).
Pope, R. M. & Shahrara, S. Possible roles of IL-12-family cytokines in rheumatoid arthritis. Nat. Rev. Rheumatol. 9, 252–256 (2013).
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).
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).
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).
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.
Khader, S. A. & Thirunavukkarasu, S. The tale of IL-12 and IL-23: a paradigm shift. J. Immunol. 202, 629–630 (2019).
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).
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).
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).
Li, Y., Wang, H., Lu, H. & Hua, S. Regulation of memory T cells by interleukin-23. Int. Arch. Allergy Immunol. 169, 157–162 (2016).
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).
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).
Neurath, M. F. IL-23 in inflammatory bowel diseases and colon cancer. Cytokine Growth Factor. Rev. 45, 1–8 (2019).
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).
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).
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).
Pflanz, S. et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 172, 2225–2231 (2004).
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).
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).
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).
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).
Kimura, D. et al. Interleukin-27-producing CD4+ T cells regulate protective immunity during malaria parasite infection. Immunity 44, 672–682 (2016).
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).
Bosmann, M. & Ward, P. A. Modulation of inflammation by interleukin-27. J. Leukoc. Biol. 94, 1159–1165 (2013).
Stumhofer, J. S. et al. A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nat. Immunol. 11, 1119–1126 (2010).
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.
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).
Jin, Y. et al. Structural insights into the assembly and activation of the IL-27 signaling complex. EMBO Rep. 23, e55450 (2022).
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).
Zhang, J. et al. Interleukin-35 in immune-related diseases: protection or destruction. Immunology 157, 13–20 (2019).
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).
Collison, L. W. et al. The composition and signaling of the IL-35 receptor are unconventional. Nat. Immunol. 13, 290–299 (2012).
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).
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).
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).
Garbers, C. et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 23, 85–97 (2012).
McGeachy, M. J., Cua, D. J. & Gaffen, S. L. The IL-17 family of cytokines in health and disease. Immunity 50, 892–906 (2019).
Gaffen, S. L. Structure and signalling in the IL-17 receptor family. Nat. Rev. Immunol. 9, 556–567 (2009).
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).
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.
Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).
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.
Zwicky, P., Unger, S. & Becher, B. Targeting interleukin-17 in chronic inflammatory disease: a clinical perspective. J. Exp. Med. 217, 20191123 (2020).
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).
Langley, R. G. et al. Secukinumab in plaque psoriasis — results of two phase 3 trials. N. Engl. J. Med. 371, 326–338 (2014).
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).
Reynolds, J. M. et al. Interleukin-17B antagonizes interleukin-25-mediated mucosal inflammation. Immunity 42, 692–703 (2015).
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).
Huang, J. et al. Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93. Immunity 54, 673–686 e674 (2021).
Saddawi-Konefka, R. et al. Nrf2 induces IL-17D to mediate tumor and virus surveillance. Cell Rep. 16, 2348–2358 (2016).
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).
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.
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).
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).
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).
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).
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.
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).
Wrenshall, L. E. et al. Identification of a cytotoxic form of dimeric interleukin-2 in murine tissues. PLoS ONE 9, e102191 (2014).
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).
Verstraete, K. et al. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat. Commun. 8, 14937 (2017).
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).
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).
Muhl, H. et al. IL-22 in tissue-protective therapy. Br. J. Pharmacol. 169, 761–771 (2013).
Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).
Boniface, K. et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin. Exp. Immunol. 150, 407–415 (2007).
Ikeuchi, H. et al. Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 52, 1037–1046 (2005).
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).
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).
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).
Nagem, R. A. et al. Crystal structure of recombinant human interleukin-22. Structure 10, 1051–1062 (2002).
Radhakrishnan, R. et al. Zinc mediated dimer of human interferon-alpha 2b revealed by X-ray crystallography. Structure 4, 1453–1463 (1996).
Karpusas, M. et al. The crystal structure of human interferon beta at 2.2-A resolution. Proc. Natl Acad. Sci. 94, 11813–11818 (1997).
Thomas, C. et al. Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell 146, 621–632 (2011).
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).
Herrington-Symes, A., Choi, J. W. & Brocchini, S. Interferon dimers: IFN-PEG-IFN. J. Drug Target. 25, 881–890 (2017).
Chang, C. H. et al. A new method to produce monoPEGylated dimeric cytokines shown with human interferon-α2b. Bioconjug Chem. 20, 1899–1907 (2009).
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).
Cavalli, G. & Dinarello, C. A. Anakinra therapy for non-cancer inflammatory diseases. Front. Pharmacol. 9, 1157 (2018).
Bui, C. B. et al. Interleukin-1 receptor antagonist protects newborn mice against pulmonary hypertension. Front. Immunol. 10, 1480 (2019).
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).
Rudloff, I. et al. Refining anti-inflammatory therapy strategies for bronchopulmonary dysplasia. J. Cell Mol. Med. 21, 1128–1138 (2017).
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).
Liu, C. et al. IL-16 signaling specifically induces STAT6 activation through CD4. Cytokine 38, 145–150 (2007).
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).
Center, D. M., Kornfeld, H. & Cruikshank, W. W. Interleukin 16 and its function as a CD4 ligand. Immunol. Today 17, 476–481 (1996).
Deckers, J. et al. Engineering cytokine therapeutics. Nat. Rev. Bioeng. 1, 286–303 (2023).
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).
Corren, J. & Ziegler, S. F. TSLP: from allergy to cancer. Nat. Immunol. 20, 1603–1609 (2019).
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).
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).
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).
Walter, M. R. & Nagabhushan, T. L. Crystal structure of interleukin 10 reveals an interferon gamma-like fold. Biochemistry 34, 12118–12125 (1995).
Rudloff, I. et al. Molecular signature of interleukin-22 in colon carcinoma cells and organoid models. Transl. Res. 216, 1–22 (2019).
Hernandez, P., Gronke, K. & Diefenbach, A. A catch-22: interleukin-22 and cancer. Eur. J. Immunol. 48, 15–31 (2018).
Poli, C. et al. IL-26 confers proinflammatory properties to extracellular DNA. J. Immunol. 198, 3650–3661 (2017).
Parker, B. S., Rautela, J. & Hertzog, P. J. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer 16, 131–144 (2016).
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).
Cersosimo, F. et al. CSF-1R in cancer: more than a myeloid cell receptor. Cancers 16, 282 (2024).
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).
Chung, C. W., Cooke, R. M., Proudfoot, A. E. & Wells, T. N. The three-dimensional solution structure of RANTES. Biochemistry 34, 9307–9314 (1995).
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).
Liu, K. et al. Structural basis of CXC chemokine receptor 2 activation and signalling. Nature 585, 135–140 (2020).
Ishimoto, N. et al. Structural basis of CXC chemokine receptor 1 ligand binding and activation. Nat. Commun. 14, 4107 (2023).
Bakouny, Z. & Choueiri, T. K. IL-8 and cancer prognosis on immunotherapy. Nat. Med. 26, 650–651 (2020).
Ostuni, M. A. et al. CX3CL1 homo-oligomerization drives cell-to-cell adherence. Sci. Rep. 10, 9069 (2020).
Tuinstra, R. L. et al. Interconversion between two unrelated protein folds in the lymphotactin native state. Proc. Natl Acad. Sci. 105, 5057–5062 (2008).
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).
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).
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).
Gaballa, J. M. et al. International nomenclature guidelines for the IL-1 family of cytokines and receptors. Nat. Immunol. 25, 581–582 (2024).
Eisenmesser, E. Z. et al. Interleukin-37 monomer is the active form for reducing innate immunity. Proc. Natl Acad. Sci. 116, 5514–5522 (2019).


















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