Elsevier

Clinical Immunology

Volume 116, Issue 3, September 2005, Pages 217-224
Clinical Immunology

Cyclophilin A may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages

https://doi.org/10.1016/j.clim.2005.05.004Get rights and content

Abstract

Cyclophilin A (CypA) levels increase in the sera and synovial fluids of rheumatoid arthritis (RA) patients, but the cell types expressing CypA and the function of CypA in the pathogenesis of RA are not known yet. Immunohistochemistry analyses revealed high level CypA staining in the macrophages in the lining layers of human RA and osteoarthritis synovium. Low level CypA staining was also detected in endothelial cells, lymphocytes, and smooth muscle cells in RA synovium. Further investigation of the CypA function using monocyte/macrophage cell lines revealed that CypA induced expression of cytokine/chemokines such as TNF-α, IL-8, MCP-1, and IL-1β and matrix metalloproteinase (MMP)-9 through a pathway that is dependent on NFκB activation. Furthermore, MMP-9 staining pattern overlapped with that of CypA in both RA and OA synovium. Our data suggest that CypA may stimulate macrophages to degrade joint cartilage via MMP-9 expression and promote inflammation via pro-inflammatory cytokine secretion.

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by the synovial inflammation that leads to the destruction of the cartilage and bone. Synovial inflammation involves lining layer thickening and infiltration of inflammatory cells into the sublining area [1], [2]. In normal joints, macrophages are resident cells and cover the synovial lining layer. The number of macrophages in the joint greatly increases in both the lining and sublining areas of RA synovium [3] and the degree of increase well correlates with the severity of cartilage destruction [4], [5], [6]. Furthermore, selective depletion of the macrophages from the synovial lining before the induction of experimental arthritis resulted in prevention of both joint inflammation and cartilage destruction [7], [8], [9]. Cartilage destruction is mediated by the extracellular matrix (ECM) degrading enzymes including serine proteases, MMPs, and the cathepsins [1]. MMP-9 levels have been shown to be elevated in the sera and synovial fluids of RA patients [10], [11].

Cyclophilin A (CypA) is a soluble ubiquitously distributed intracellular protein belonging to the immunophilin family [12]. Additional experiments, however, have implicated CypA in inflammation since it is secreted from smooth muscle cells and macrophages in response to oxidative stress and lipopolysaccharide (LPS) [13], [14], [15]. Platelets also secrete CypA upon activation [16]. Furthermore, CypA has been detected to be elevated in the serum of sepsis patients and the synovial fluids of RA patients [17], [18]. In inflammatory diseases such as atherosclerosis, CypA works as a proinflammatory cytokine and activates endothelial cells to produce inflammatory mediators and undergo apoptosis [14], [19]. Recently, CypA was reported to be related to the growth and differentiation of other cells, such as human embryonic nerve cells [20].

Although the pro-inflammatory activities of CypA are well known, the role of CypA in the pathogenesis of RA is not specifically known. We analyzed synovial tissues from human RA patients to reveal the cell types expressing CypA. We also tested the possible role of CypA during the development of RA using human and murine monocytic cell lines.

Section snippets

Monoclonal antibodies, cell lines, and reagents

Monoclonal antibodies (mAbs) to CD68 (KP1), CD3 (F7.2.38), and α-actin (1A4) and rabbit polyclonal antibody to von Willebrand factor (vWF) (N1505) were purchased from DAKO (Glostrup, Denmark); mouse polyclonal antibody to CypA from BIOMOL International (USA); rabbit polyclonal antibody to IκB and mAb to phospho-IκB (Ser32/36) (5A5) from Cell Signaling (USA); mAb to MMP-3 (SL-1 IID4) and rabbit polyclonal antibody to MMP-9 from Chemicon (USA). Human monocytic leukemia cell line THP-1 [21] and

CypA expression is concentrated in areas enriched in macrophages and endothelial cells in RA synovium

Synovial tissues were obtained from RA and osteoarthritis (OA) patients and CypA, CD68 (a macrophage marker), and von Willebrand factor (vWF) (an endothelial cell marker) expression patterns were analyzed using immunohistochemistry (Fig. 1). In RA synovium, CypA staining was detected in the macrophages in the lining layer and the microvessel endothelial cells in the sublining area (compare panels A with B and C). CypA expression was also detected in the macrophages in the sublining area in

Acknowledgments

This work was supported by grants (R01-2003-000-10887-0 and R12-2003-002-04002-0) from the Basic Research Program of the Korea Science and Engineering Foundation.

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