In this review, published in Arthritis Research & Therapy Cem Gabay and Iain McInnes present the biology and relevant pathophysiology of several novel cytokines, with focus on their involvement in rheumatic diseases.
This list includes the interleukin (IL)-1 superfamily (IL-18 and IL-33), the IL-12 superfamily (IL-27 and IL-35), the IL-2 superfamily (IL-15 and IL-21), and IL-17.
Recent evidence indicates that single-cytokine targeting is particularly valuable in several rheumatic diseases, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and the spondyloarthropathies. This for example includes the success of TNFα-blocking therapies in RA.
IL-15 is produced mostly by dendritic cells, monocytes, and epithelial cells, and its production is usually induced by viral infections. This cytokines regulates T and natural killer (NK) cell activation and proliferation. It stimulates T cell proliferation and activates NK cells. As per the authors, it also promotes neutrophil activation, cytokine and chemokine release, degranulation, and phagocytic function.
IL-17 plays an essential role in many chronic inflammatory and autoimmune diseases. IL-17 induces the production of IL-1, IL-6, TNF-α, inducible NO synthase, matrix metalloproteinases (MMPs), and is particularly potent in activating neutrophils. Recent evidence indicates that this cytokine is a promising therapeutic target in several chronic inflammatory diseases.
IL-21, as discussed by the authors is a pro-inflammatory cytokine, involved in the pathogenesis of several rheumatic diseases. This cytokine preferentially promotes T helper (Th)17 commitment and expansion. Also it is a major inducer of B-cell activation and differentiation, and plasma cell generation. It also mediates broad effects upon T-cell activation and on NK-cell and NKT-cell maturation and activation.
IL-33, is considered as an ‘alarmin’ mediator released following cell necrosis and alerting the immune system to tissue damage or stress. The cytokine potently up-regulates Th2 cytokine production and is involved in the pathogenesis of Th2-related disease such as asthma, atopic dermatitis and anaphylaxis.
Cem Gabay and Iain McInnes conclude that in the future, rational targeting using pharmacogenomic or protein biomarker-based approaches will enrich high-hurdle response rates. Moreover, rational targeting of combinations of several cytokines, driven by biomarker profiles that define specific functional moieties and patients, may become possible.
Source: Arthritis Res Ther 2009, 11:230
Read more: Arthritis Research & Therapy