The history of discovery of Interleukin-1: a fundamental cytokine of the innate immune response

Main Article Content

Veronica Vivona
Luca Lepore
Giorgia Bilato
Lorenzo Mortara
Andrea De Lerma Barbaro


Interleukin-1, IL1, leukocytic pyrogen, endogenous pyrogen, IL-1 family molecules, alarmins


The discovery of IL-1 marked the beginning of research on soluble mediators of the immune response but also the initiation of studies on inflammatory responses to tissue damage. Initially referred to as endogenous leukocyte pyrogen (from the Greek word ‘pyr’ for fire), due to its role as a fever inducer, the study of this molecule led to the identification of numerous other related soluble factors, which together take the IL-1 family name. Additionally, the study of IL-1 provided the starting point for the characterization of numerous structurally and functionally related receptors that play crucial roles in the regulation of immune responses. In fact, the IL-1 family plays a key role in inflammation, in the response to microbes, and acts as an inducer of both autoimmune and autoinflammatory pathologies, as well as being associated with cancer. In this last context, both pro-tumor and anti-tumor roles of IL1 family members have been highlighted. Therefore, IL-1 family molecules have many aspects still to be studied today and many researchers are actively involved in this line of investigation for the potential treatment of various diseases.

Abstract 50 | PDF Downloads 94


1. Beeson PB. Temperature-elevating effect of a substance obtained from polymorphonuclear leucocytes. J Clin Invest 1948; 27(4):524.
2. Dinarello CA. The history of fever, leukocytic pyrogen and interleukin-1. Temperature (Austin) 2015; 2(1):8–16.
3. Atkins E. Fever: the old and the new. J Infect Dis 1984; 149(3):339–48.
4. Bodel P, Atkins E. Release of endogenous pyrogen by human monocytes. N Engl J Med 1967; 276(18):1002–8.
5. Gery I, Gershon RK, Waksman BH. Potentiation of the T-lymphocyte response to mitogens. I. The responding cell. J Exp Med 1972; 136(1):128–42.
6. Oppenheim JJ, Gery I. Interleukin 1 is more than an interleukin. Immunol Today 1982; 3(4):113–9.
7. Dinarello CA, Goldin NP, Wolff SM. Demonstration and characterization of two distinct human leukocytic pyrogens. J Exp Med 1974; 139(6):1369–81.
8. Revised nomenclature for antigen-nonspecific T cell proliferation and helper factors. J Immunol 1979; 123(6):2928–9.
9. Rosenwasser LJ, Dinarello CA, Rosenthal AS. Adherent cell function in murine T-lymphocyte antigen recognition. IV. Enhancement of murine T-cell antigen recognition by human leukocytic pyrogen. J Exp Med 1979; 150(3):709–14.
10. Dinarello CA. IL-1: discoveries, controversies and future directions. Eur J Immunol 2010; 40(3):599–606.
11. Damais C, Riveau G, Parant M, Gerota J, Chedid L. Production of lymphocyte activating factor in the absence of endogenous pyrogen by rabbit or human leukocytes stimulated by a muramyl dipeptide derivative. Int J Immunopharmacol 1982; 4(5):451–62.
12. Murphy PA, Chesney PJ, Wood WB Jr. Purification of an endogenous pyrogen, with an appendix on assay methods. Ciba Found Symp 1971:59–79.
13. Murphy PA, Cebula TA, Levin J, Windle BE. Rabbit macrophages secrete two biochemically and immunologically distinct endogenous pyrogens. Infect Immun 1981; 34(1):177–83.
14. Lomedico PT, Gubler U, Hellmann CP, et al. Cloning and expression of murine interleukin-1 cDNA in Escherichia coli. Nature 1984; 312(5993):458–62.
15. Auron PE, Webb AC, Rosenwasser LJ, et al. Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci USA 1984; 81(24):7907–11.
16. March CJ, Mosley B, Larsen A, et al. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature 1985; 315(6021):641–7.
17. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975; 72:3666–70
18. Kustrimovic N, Gallo D, De Lerma Barbaro A, Piantanida E, Mortara L, Tanda ML. The discovery of TNF-alpha: a historical perspective. Med Histor 2023; 7(2):e2023037.
19. Dinarello CA, Bodel PT, Atkins E. The role of the liver in the production of fever and in pyrogenic tolerance. Trans Assoc Am Physicians 1968; 81:334–44.
20. Dinarello CA, Renfer L, Wolff SM. Human leukocytic pyrogen: purification and development of a radioimmunoassay. Proc Natl Acad Sci USA 1977; 74(10):4624–7.
21. Dinarello CA. Interleukin-1 and the effects of cyclooxygenase inhibitors on its biological activities. Bull N Y Acad Med 1989; 65(1):80–92.
22. Mizel SB, Mizel D. Purification to apparent homogeneity of murine interleukin 1. J Immunol 1981; 126(3):834–7.
23. Dinarello CA, Cannon JG, Mier JW, et al. Multiple biological activities of human recombinant interleukin 1. J Clin Invest 1986; 77(6):1734–9.
24. Sims JE, March CJ, Cosman D, et al. cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science 1988; 241(4865):585–9.
25. Greenfeder SA, Nunes P, Kwee L, Labow M, Chizzonite RA, Ju G. Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem 1995; 270(23):13757–65.
26. Højen JF, Kristensen MLV, McKee AS, et al. IL-1R3 blockade broadly attenuates the functions of six members of the IL-1 family, revealing their contribution to models of disease. Nat Immunol 2019; 20(9):1138–49.
27. Boraschi D, Tagliabue A. The interleukin-1 receptor family. Semin Immunol 2013; 25(6):394–407.
28. Balavoine JF, de Rochemonteix B, Williamson K, Seckinger P, Cruchaud A, Dayer JM. Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urine-derived human interleukin 1 and inhibitor(s). J Clin Invest 1986; 78(4):1120–4.
29. Dayer JM, Oliviero F, Punzi L. A Brief History of IL-1 and IL-1 Ra in Rheumatology. Front Pharmacol 2017; 8:293.
30. Hannum CH, Wilcox CJ, Arend WP, et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 1990; 343(6256):336–40.
31. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol 2010; 10(2):89–102.
32. McMahan CJ, Slack JL, Mosley B, et al. A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J 1991; 10(10):2821–32.
33. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 2018; 281(1):8–27.
34. Peters VA, Joesting JJ, Freund GG. IL-1 receptor 2 (IL-1R2) and its role in immune regulation. Brain Behav Immun 2013; 32:1–8.
35. Vasanthakumar A, Kallies A. Interleukin (IL)-33 and the IL-1 Family of Cytokines-Regulators of Inflammation and Tissue Homeostasis. Cold Spring Harb Perspect Biol 2019; 11(3):a028506.
36. Dayer JM, Graham R, Russell G, Krane SM. Collagenase production by rheumatoid synovial cells: stimulation by a human lymphocyte factor. Science 1977; 195(4274):181–3.
37. Dayer JM, Robinson DR, Krane SM. Prostaglandin production by rheumatoid synovial cells: stimulation by a factor from human mononuclear Cells. J Exp Med 1977; 145(5):1399–404.
38. Mizel SB, Dayer JM, Krane SM, Mergenhagen SE. Stimulation of rheumatoid synovial cell collagenase and prostaglandin production by partially purified lymphocyte-activating factor (interleukin 1). Proc Natl Acad Sci USA 1981; 78(4):2474–7.
39. Seitz M, Loetscher P, Dewald B, et al. Interleukin 1 (IL-1) receptor antagonist, soluble tumor necrosis factor receptors, IL-1 beta, and IL-8--markers of remission in rheumatoid arthritis during treatment with methotrexate. J Rheumatol 1996; 23(9):1512–6.
40. Arend WP. Cytokine imbalance in the pathogenesis of rheumatoid arthritis: the role of interleukin-1 receptor antagonist. Semin Arthritis Rheum 2001; 30(5 Suppl 2):1–6.
41. Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11(8):633–52.
42. Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell 2010; 140(6):784–90.
43. Zhang QY, Ye XP, Zhou Z, et al. Lymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto’s thyroiditis. Nat Commun 2022; 13(1):775.
44. Mortara L, Coco G, Gatti L, Piantanida E, Gallo D. Analysis of Graves’ disease from the origins to the current historical evolution: The history of Graves’ disease discovery and treatment. Med Histor 2022; 5(3):e2021030.
45. Gallo D, Mortara L, Gariboldi MB, et al. Immunomodulatory effect of vitamin D and its potential role in the prevention and treatment of thyroid autoimmunity: a narrative review. J Endocrinol Invest 2020; 43(4):413–29.
46. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002; 10(2):417–26.
47. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 2004; 20(3):319–25.
48. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009; 27:229–65.
49. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1):57–70.
50. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5):646–74.
51. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008; 454(7203):436–44.
52. Mantovani A, Barajon I, Garlanda C. IL-1 and IL-1 regulatory pathways in cancer progression and therapy. Immunol Rev 2018; 281(1):57–61.
53. Giavazzi R, Garofalo A, Bani MR, et al. Interleukin 1-induced augmentation of experimental metastases from a human melanoma in nude mice. Cancer Res 1990; 50(15):4771–5.
54. Condamine T, Mastio J, Gabrilovich DI. Transcriptional regulation of myeloid-derived suppressor cells. J Leukoc Biol 2015; 98(6):913–22.
55. Virgilio T, Bordini J, Cascione L, et al. Subcapsular Sinus Macrophages Promote Melanoma Metastasis to the Sentinel Lymph Nodes via an IL1α-STAT3 Axis. Cancer Immunol Res 2022; 10(12):1525–41.
56. Ghiringhelli F, Apetoh L, Tesniere A, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 2009; 15(10):1170–8.
57. Balza E, Zanellato S, Poggi A, Reverberi D, Rubartelli A, Mortara L. The therapeutic T-cell response induced by tumor delivery of TNF and melphalan is dependent on early triggering of natural killer and dendritic cells. Eur J Immunol 2017; 47(4):743–53.
58. Mortara L, Orecchia P, Castellani P, Borsi L, Carnemolla B, Balza E. Schedule-dependent therapeutic efficacy of L19mTNF-α and melphalan combined with gemcitabine. Cancer Med 2013; 2(4):478–87
59. Balza E, Carnemolla B, Mortara L, et al. Therapy-induced antitumor vaccination in neuroblastomas by the combined targeting of IL-2 and TNFalpha. Int J Cancer 2010; 127(1):101–10.
60. Croce M, Meazza R, Orengo AM, et al. Sequential immunogene therapy with interleukin-12- and interleukin-15-engineered neuroblastoma cells cures metastatic disease in syngeneic mice. Clin Cancer Res 2005; 11(2 Pt 1):735–42.
61. Banerjee M, Saxena M. Interleukin-1 (IL-1) family of cytokines: role in type 2 diabetes. Clin Chim Acta 2012; 413(15-16):1163–70.
62. Huang G, Li M, Tian X, Jin Q, Mao Y, Li Y. The Emerging Roles of IL-36, IL-37, and IL-38 in Diabetes Mellitus and its Complications. Endocr Metab Immune Disord Drug Targets 2022; 22(10):997–1008.
63. Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA. Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease. Circ Res 2020; 126(9):1260–80.

Most read articles by the same author(s)