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IL-32, a proinflammatory cytokine in rheumatoid arthritis
Leo A. B. Joosten*,,
Mihai G. Netea,,
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 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, IL-1,IL-6, and chemokines. We investigated whether IL-32 is expressedin the synovia of patients with rheumatoid arthritis (RA) andstudied associations with disease severity and the presenceof other cytokines. Immunohistochemistry revealed that IL-32is highly expressed in RA synovial tissue biopsies, whereasIL-32 was not observed in synovial tissues from patients withosteoarthritis. Moreover, in synovial biopsies from 29 RA patientswith active disease, the level of IL-32 staining correlatedwith erythrocyte sedimentation rate, a marker of systemic inflammation(R = 0.63 and P < 0.0003). Synovial staining of IL-32 alsocorrelated with indices of synovial inflammation (R = 0.80 andP < 0.0001) as well as synovial presence of TNF (R = 0.68and P < 0.004), IL-1 (R = 0.79 and P < 0.0001), and IL-18(R = 0.82 and P < 0.001). IL-32 was a potent inducer of prostaglandinE2 release in mouse macrophages and human blood monocytes, animportant property for inflammation. After the injection ofhuman IL-32 into the knee joints of naïve mice, joint swelling,with pronounced influx of inflammatory cells and cartilage damage,was observed. In TNF-deficient mice, IL-32-driven joint swellingwas absent and cell influx was markedly reduced, but loss ofproteoglycan was unaffected, suggesting that IL-32 activityis, in part, TNF-dependent. IL-32, strongly associated withTNF, IL-1, and IL-18, appears to play a role in human RA andmay be a novel target in autoimmune diseases.
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.
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
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,
Mihai G. Netea
,
,
Soo-Hyun Kim
, IL-1
, 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
into the knee joints of naïve mice, joint swelling, with pronounced influx of inflammatory cells and cartilage damage, was observed. In TNF
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: 
