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PNAS 103 (9): 3298-3303

Copyright © 2006 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / IMMUNOLOGY

IL-32, a proinflammatory cytokine in rheumatoid arthritis

Leo A. B. Joosten*,{dagger}, Mihai G. Netea{ddagger},§, Soo-Hyun Kim§, Do-Young Yoon, Birgitte Oppers-Walgreen*, Timothy R. D. Radstake*,||, Pilar Barrera||, Fons A. J. van de Loo*, Charles A. Dinarello§,**, and Wim B. van den Berg*

*Rheumatology Research and Advanced Therapeutics and Departments of ||Rheumatology and {ddagger}Internal Medicine, Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands; §Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262; and Department of Biology, Korea Research Institute of Biotechnology, Taejeon 305-600, Korea

Contributed by Charles A. Dinarello, December 28, 2005

Abstract: IL-32 is a recently discovered cytokine that induces TNF{alpha}, IL-1beta, IL-6, and chemokines. We investigated whether IL-32 is expressed in the synovia of patients with rheumatoid arthritis (RA) and studied associations with disease severity and the presence of other cytokines. Immunohistochemistry revealed that IL-32 is highly expressed in RA synovial tissue biopsies, whereas IL-32 was not observed in synovial tissues from patients with osteoarthritis. Moreover, in synovial biopsies from 29 RA patients with active disease, the level of IL-32 staining correlated with erythrocyte sedimentation rate, a marker of systemic inflammation (R = 0.63 and P < 0.0003). Synovial staining of IL-32 also correlated with indices of synovial inflammation (R = 0.80 and P < 0.0001) as well as synovial presence of TNF{alpha} (R = 0.68 and P < 0.004), IL-1beta (R = 0.79 and P < 0.0001), and IL-18 (R = 0.82 and P < 0.001). IL-32 was a potent inducer of prostaglandin E2 release in mouse macrophages and human blood monocytes, an important property for inflammation. After the injection of human IL-32{gamma} into the knee joints of naïve mice, joint swelling, with pronounced influx of inflammatory cells and cartilage damage, was observed. In TNF{alpha}-deficient mice, IL-32-driven joint swelling was absent and cell influx was markedly reduced, but loss of proteoglycan was unaffected, suggesting that IL-32 activity is, in part, TNF{alpha}-dependent. IL-32, strongly associated with TNF{alpha}, IL-1beta, and IL-18, appears to play a role in human RA and may be a novel target in autoimmune diseases.

Key Words: autoimmune • inflammation • tumor necrosis factor


Author contributions: L.A.B.J., M.G.N., P.B., F.A.J.v.d.L., C.A.D., and W.B.v.d.B. designed research; L.A.B.J., M.G.N., B.O.-W., and F.A.J.v.d.L. performed research; S.-H.K., D.-Y.Y., and C.A.D. contributed new reagents/analytic tools; L.A.B.J., M.G.N., D.-Y.Y., B.O.-W., T.R.D.R., P.B., F.A.J.v.d.L., C.A.D., and W.B.v.d.B. analyzed data; and L.A.B.J., M.G.N., S.-H.K., C.A.D., and W.B.v.d.B. wrote the paper.

Conflict of interest statement: No conflicts declared.

{dagger}To whom correspondence may be addressed at: Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. E-mail: l.joosten{at}reuma.umcn.nl

**To whom correspondence may be addressed. E-mail: cdinarello{at}mac.com

© 2006 by The National Academy of Sciences of the USA


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