The interleukin-12 family of cytokines: Therapeutic targets for inflammatory disease mediation

The interleukin (IL)-12 family of cytokines, including IL-12 and IL-23, are important mediators of immune-mediated inflammatory diseases such as psoriasis, multiple sclerosis, rheumatoid arthritis, and Crohn’s disease. Interleukin-12 and IL-23 are heterodimeric proteins composed of the common subunit IL-12 p40, which interacts with the IL-12Rb1 receptor, and the cytokine-specific subunits IL-12 p35 and IL-23 p19, respectively. The cytokines are proinflammatory factors linking innate and adaptive immune responses via the induction and differentiation of the T helper cell 1 pathway. Interleukin-12 and IL-23 target different subpopulations of T cells and antigen-presenting cells, as evidenced by their slightly different, but possibly clinically significant, characteristics and functions. Because both share the p40 subunit, the use of anti-IL-12 antibodies may not be as clinically effective as the use of anti-IL-12 p40 antibodies, since both IL-12 and IL-23 share the subunit, which compete, for the IL-12Rb1 receptor. Also, while IL-12 is a key factor that drives T helper cell 1 responses and interferon-gamma production in the early phases of the immune responses, it may play a relatively minor immunoregulatory role in late-stage inflammation at the point when IL-23 strongly supports the inflammatory process. Thus, direct IL-23 blockade may be key in treating some inflammatory autoimmune diseases as we further define the roles and functions of IL-12 and IL-23. Research into Abbreviations: AIA, autoimmune arthritis; APC, antigen-presenting cell; CD, Crohn’s disease; CIA, collagen-induced arthritis; EAE, experimental autoimmune encephalomyelitis; EPI3, Epstein-Barr virus-induced gene 3; G-CSF, granulocyte-colony stimulating factor; IBD, inflammatory bowel disease; IFN-b, interferon-beta; IFN-g, interferon-gamma; IL, interleukin; IMID, immune-mediated inflammatory disease; JAK, Janus kinase; mAb, monoclonal antibody; MS, multiple sclerosis; NK, natural killer; OA, osteoarthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SCID, severe combined immunodeficiency disease; STAT, signal transducer and activator of transcription; TH1, T helper cell 1; TH2, T helper cell 2; TNBS, 2,4,6-trinitrobenzene sulfonic acid; TNF, tumor necrosis factor. * Corresponding author. University of Pittsburgh School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Scaife Hall, Room 566, 3550 Terrace St., Pittsburgh, PA 15261, USA. Tel.: C1 412 648 9573; fax: C1 412 383 8913. E-mail address: [email protected] (S.E. Plevy). 1529-1049/05/$ e see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.cair.2005.06.003 226 A.M. Barrie, S.E. Plevy/Clin. Applied Immunol. Rev. 5 (2005) 225e240 the function and regulation of IL-12 and IL-23 is a promising area of study for inflammatory disease mediation, and inhibition of their actions may have clinical therapeutic applications. 2005 Elsevier Inc. All rights reserved.