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Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells

McGettrick, H.M and Smith, E and Filer, A and Kissane, S and Salmon, M and Buckley, Christopher D. and Rainger, G. Ed and Nash, Gerard B. (2009) Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells. European Journal of Immunology, 39 (1). pp. 113-125. ISSN 0014-2980

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URL of Published Version: http://www3.interscience.wiley.com/cgi-bin/fulltext/121616868/PDFSTART

Identification Number/DOI: 10.1002/eji.200838232

We examined the hypothesis that stromal fibroblasts modulate the ability of endothelial cells (EC) to recruit lymphocytes in a site-specific manner. PBL were perfused over HUVEC that had been cultured with fibroblasts isolated from the inflamed synovium or the skin of patients with rheumatoid arthritis or osteoarthritis, or from normal synovium, with or without exposure to the inflammatory cytokines TNF-a+IFN-c. Fibroblasts from inflamed synovium, but no others, caused unstimulated HUVEC to bind flowing lymphocytes. This adhesion was supported by a4b1-VCAM-1 interaction and stabilised by activation of PBL through CXCR4–CXCL12. Antibody neutralisation of IL-6 during co-culture effectively
abolished the ability of EC to bind lymphocytes. Cytokine-stimulated EC supported high levels of lymphocyte adhesion, through the presentation of VCAM-1, E-selectin and chemokine(s) acting through CXCR3. Interestingly, co-culture with dermal fibroblasts caused a marked reduction in cytokine-induced adhesion, while synovial fibroblasts had variable effects depending on their source. In the dermal co-cultures, neutralisation of IL-6 or TGF-b caused partial recovery of cytokine-induced lymphocyte adhesion; this was complete when both were neutralised. Exogenous IL-6 was also found to inhibit response to TNF-a+IFN-c. Normal stromal fibroblasts appear to regulate the cytokine-sensitivity of vascular endothelium, while fibroblasts associated with chronic inflammation bypass this and develop a directly inflammatory phenotype. Actions of IL-6 might be pro-inflammatory or anti-inflammatory, depending on the local milieu.

Type of Work:Article
Date:07 January 2009 (Publication)
School/Faculty:Schools (1998 to 2008) > School of Medicine
Department:Centre for Cardiovascular Sciences, Centre for Immune Regulation
Subjects:R Medicine (General)
Institution:University of Birmingham
Copyright Holders:John Wiley and Sons
ID Code:161
Refereed:YES
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