IL-12, IL-23 and IL-17 in IBD: Immunobiology and Therapeutic Targeting

Overview

Journal Nat Rev Gastroenterol Hepatol

Specialty Gastroenterology

Date 2018 Nov 28

PMID 30478416

Citations 201

Authors

Alexander R Moschen

Herbert Tilg

Tim Raine

Affiliations

Soon will be listed here.

Abstract

IL-12 and IL-23 are closely related cytokines with important roles in the regulation of tissue inflammation. Converging evidence from studies in mice, human observational studies and population genetics supports the importance of these cytokines in the regulation of mucosal inflammation in the gut in particular. Ustekinumab, a therapeutic antibody targeting both cytokines is now widely licensed for the treatment of Crohn's disease, including in Europe, the USA, Canada and Japan, whilst agents targeting IL-23 specifically are in late-phase clinical trials. We review the emerging understanding of the biology of IL-12 and IL-23, as well as that of their major downstream cytokines, including IL-17. In particular, we discuss how their biology has influenced the development of clinical trials and therapeutic strategies in IBD, as well as how findings from clinical trials, at times surprising, have in turn refocused our understanding of the underlying biology.

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References

Duerr R, Taylor K, Brant S, Rioux J, Silverberg M, Daly M . A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006; 314(5804):1461-3. PMC: 4410764. DOI: 10.1126/science.1135245. View

Macatonia S, Hosken N, Litton M, Vieira P, Hsieh C, Culpepper J . Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995; 154(10):5071-9. View

Szabo S, Kim S, Costa G, Zhang X, Fathman C, Glimcher L . A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000; 100(6):655-69. DOI: 10.1016/s0092-8674(00)80702-3. View

Segal B, Dwyer B, Shevach E . An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med. 1998; 187(4):537-46. PMC: 2212155. DOI: 10.1084/jem.187.4.537. View

McIntyre K, Shuster D, Gillooly K, Warrier R, Connaughton S, Hall L . Reduced incidence and severity of collagen-induced arthritis in interleukin-12-deficient mice. Eur J Immunol. 1996; 26(12):2933-8. DOI: 10.1002/eji.1830261219. View

Neurath M, Fuss I, Kelsall B, Stuber E, Strober W . Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995; 182(5):1281-90. PMC: 2192205. DOI: 10.1084/jem.182.5.1281. View

Fuss I, Marth T, Neurath M, Pearlstein G, Jain A, Strober W . Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice. Gastroenterology. 1999; 117(5):1078-88. DOI: 10.1016/s0016-5085(99)70392-6. View

Cua D, Sherlock J, Chen Y, Murphy C, Joyce B, Seymour B . Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003; 421(6924):744-8. DOI: 10.1038/nature01355. View

Yen D, Cheung J, Scheerens H, Poulet F, Mcclanahan T, McKenzie B . IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006; 116(5):1310-6. PMC: 1451201. DOI: 10.1172/JCI21404. View

10.

Patel D, Kuchroo V . Th17 Cell Pathway in Human Immunity: Lessons from Genetics and Therapeutic Interventions. Immunity. 2015; 43(6):1040-51. DOI: 10.1016/j.immuni.2015.12.003. View

11.

Mannon P, Fuss I, Mayer L, Elson C, Sandborn W, Present D . Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med. 2004; 351(20):2069-79. DOI: 10.1056/NEJMoa033402. View

12.

Vignali D, Kuchroo V . IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012; 13(8):722-8. PMC: 4158817. DOI: 10.1038/ni.2366. View

13.

Collison L, Delgoffe G, Guy C, Vignali K, Chaturvedi V, Fairweather D . The composition and signaling of the IL-35 receptor are unconventional. Nat Immunol. 2012; 13(3):290-9. PMC: 3529151. DOI: 10.1038/ni.2227. View

14.

Hunter C, Kastelein R . Interleukin-27: balancing protective and pathological immunity. Immunity. 2012; 37(6):960-9. PMC: 3531794. DOI: 10.1016/j.immuni.2012.11.003. View

15.

Bloch Y, Bouchareychas L, Merceron R, Skladanowska K, Van den Bossche L, Detry S . Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1. Immunity. 2017; 48(1):45-58.e6. PMC: 5773378. DOI: 10.1016/j.immuni.2017.12.008. View

16.

Thierfelder W, Van Deursen J, Yamamoto K, Tripp R, Sarawar S, Carson R . Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996; 382(6587):171-4. DOI: 10.1038/382171a0. View

17.

Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J . A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002; 168(11):5699-708. DOI: 10.4049/jimmunol.168.11.5699. View

18.

Mortha A, Chudnovskiy A, Hashimoto D, Bogunovic M, Spencer S, Belkaid Y . Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science. 2014; 343(6178):1249288. PMC: 4291125. DOI: 10.1126/science.1249288. View

19.

Maloy K, Kullberg M . IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 2008; 1(5):339-49. DOI: 10.1038/mi.2008.28. View

20.

Hilliard B, Mason N, Xu L, Sun J, Lamhamedi-Cherradi S, Liou H . Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. J Clin Invest. 2002; 110(6):843-50. PMC: 151124. DOI: 10.1172/JCI15254. View