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* Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Department of Pathology, Yale University, New Haven, CT 06520; and
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710
Macrophages are important mediators of chronic inflammation and are prominent in the synovial lining and sublining of patients with rheumatoid arthritis (RA). Recently, we demonstrated increased TLR2 and TLR4 expression and increased response to microbial TLR2 and TLR4 ligands in macrophages from the joints of RA. The current study characterized the expression of the 96-kDa heat shock glycoprotein (gp96) in the joints of RA and its role as an endogenous TLR ligand to promote innate immunity in RA. gp96 was increased in RA compared with osteoarthritis and arthritis-free control synovial tissues. The expression of gp96 strongly correlated with inflammation and synovial lining thickness. gp96 was increased in synovial fluid from the joints of RA compared with disease controls. Recombinant gp96 was a potent activator of macrophages and the activation was mediated primarily through TLR2 signaling. The cellular response to gp96 was significantly stronger with RA synovial macrophages compared with peripheral blood monocytes from RA or healthy controls. The transcription of TLR2, TNF-
, and IL-8, but not TLR4, was significantly induced by gp96, and the induction was significantly greater in purified RA synovial macrophages. The expression of TLR2, but not TLR4, on synovial fluid macrophages strongly correlated with the level of gp96 in the synovial fluid. The present study documents the potential role of gp96 as an endogenous TLR2 ligand in RA and provides insight into the mechanism by which gp96 promotes the chronic inflammation of RA, identifying gp96 as a potential new therapeutic target.
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 by National Institutes of Health Grants AR055240, AR048269 (to R.M.P.), and CA104392 (to C.V.N.) and a Within Our Reach Award from the American College of Rheumatology (to R.M.P.).
2 Address correspondence and reprint requests to Dr. Richard M. Pope, Division of Rheumatology, Northwestern University Feinberg School of Medicine and the Jesse Brown Veterans Affairs Chicago Healthcare System, 240 East Huron, McGaw M300, Chicago, IL 60611. E-mail address: rmp158{at}northwestern.edu
3 Abbreviations used in this paper: RA, rheumatoid arthritis; HSP, heat shock protein; gp96, 96-kDa heat shock glycoprotein; OA, osteoarthritis; PGN-SA, peptidoglycan from Staphylococcus aureus; SF, synovial fluid; LTA-SA, lipoteichoic acid from S. aureus; LPS-UP, ultrapure LPS; IP, interactive precipitation.
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  R. Suriano, S. K Ghosh, D. Chaudhuri, A. Mittelman, A. Banerjee, and R. K Tiwari Sialic acid content of tissue-specific gp96 and its potential role in modulating gp96-macrophage interactions Glycobiology, December 1, 2009; 19(12): 1427 - 1435. [Abstract] [Full Text] [PDF]
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