Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis.

Abstract

Experimental evidence points to the importance of the cytokine interleukin-17A (IL-17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL-17A is produced by many other cell types including CD8(+) T cells and γδ T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL-17A up-regulates expression of numerous inflammation-related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL-17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro-inflammatory cytokines, including tumour necrosis factor. Several direct IL-17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL-17A in disease pathogenesis, although levels of response are not predicted by pre-clinical findings. IL-17A inhibitors produced rapid down-regulation of the psoriasis gene signature and high clinical response rates in patients with moderate-to-severe plaque psoriasis, consistent with an important role for IL-17A in psoriasis pathogenesis. Clinical response rates with IL-17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL-17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL-17A in these diseases.

• Authors: Bruce W Kirkham, Arthur Kavanaugh, Kristian Reich
• Journal: Immunology (Immunology) Vol. 141 Issue 2 Pg. 133-42 (Feb 2014) ISSN: 1365-2567 [Electronic] England
• PMID: 23819583 (Publication Type: Journal Article, Review)
• Copyright: © 2013 John Wiley & Sons Ltd.

Chemical References

• Interleukin-17
• Receptors, Interleukin-17

Topics

• Animals
• Arthritis, Psoriatic (drug therapy, etiology, immunology)
• Arthritis, Rheumatoid (drug therapy, etiology, immunology)
• Clinical Trials as Topic
• Humans
• Interleukin-17 (antagonists & inhibitors, physiology)
• Psoriasis (drug therapy, etiology, immunology)
• Receptors, Interleukin-17 (physiology)
• Signal Transduction (physiology)