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IL-17 Induces Monocyte Migration in Rheumatoid Arthritis¹

Shiva Shahrara^2,*, Sarah R. Pickens^*, Andrea Dorfleutner^* and Richard M. Pope^*,

^* Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL 60611; and Jesse Brown VA Chicago Healthcare System, Chicago, IL 60611

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is in part mediated by the migration of monocytes from blood to RA synovial tissue, where they differentiate into macrophages and secrete inflammatory cytokines and chemokines. The T cell cytokine IL-17 is expressed in the RA synovial tissue and synovial fluid. To better understand the mechanism by which IL-17 might promote inflammation, its role in monocyte trafficking was examined. In vivo, IL-17 mediates monocyte migration into sponges implanted into SCID mice. In vitro, IL-17 was chemotactic, not chemokinetic, for monocytes at the concentrations detected in the RA synovial fluid. Further, IL-17-induced monocyte migration was mediated by ligation to IL-17RA and RC expressed on monocytes and was mediated through p38MAPK signaling. Finally, neutralization of IL-17 in RA synovial fluid or its receptors on monocytes significantly reduced monocyte migration mediated by RA synovial fluid. These observations suggest that IL-17 may be important in recruiting monocytes into the joints of patients with RA, supporting IL-17 as a therapeutic target in RA.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by awards from the National Institutes of Health (AR049353, AR048269, and AR055240) as well as grants from the American College of Rheumatology Within Our Reach.

² Address correspondence and reprint requests to Dr. Shiva Shahrara, Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Rheumatology, McGaw Pavilion, 240 East Huron, Suite M300, Chicago, Illinois 60611. E-mail address: s-shahrara{at}northwestern.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; p, phospho; HMVEC, human microvascular endothelial cell; HPF, high power field; SF, synovial fluid; OA, osteoarthritis.