Bik, Magadelena Anna (2009)
Ph.D. thesis, University of Birmingham.
Fibroblasts are important regulators of inflammatory processes. The phenotype of fibroblasts differ according to anatomical site which may dtermine immune functions such as leukocyte accumulation and predilection for inflammatory disease in certain tissues. This thesis describes the expression profile and explores the function of a family of immunomodulatory proteins (galectins) in fibroblasts from rhematoid arthritis patients. Synovial fibroblasts were found to differ significantly from bone marrow and skin fibroblasts with higher expression of galectin-9 and galectin-12 in synovial fibroblasts. Galectin-9 and galectin-3 expression was also examined in situ in synovial tissue from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Expression of both galectins were higher in RA synovial tissue compared to OA but not in synovial fibroblasts cultured in vitro. Galectin-3 expression seemed to be controlled by epigenetic factors (methylation) but not cytokine stimulation. Galectin-9 production was up-regulated by interferon-y, interleukin-1b and ligands for Toll-like receptors 3 (TLR3) and 4 (TLR4). It was found that intracellular presence of galectin-9 in RA synovial firboblasts increased their resistance to apoptosis. Galectin-3 level are increased in teh joints of patients with rheumatoid arthritis. Studies on the effect and mechanism of galectin-3 action on fibroblasts revealed that exogenously added galectin-3 induced production of cytokines (IL-6) from synovial and skin fibroblasts but the production of moncyte attracting chemokines (CCL5, CCL2) was induced uniquely in fibroblasts derived from teh synovium. Different signalling pathways mediated the secretion of those mediators. IL-6 release depended on MAP kinases p38, ERK and JNK as well as NFkB transcription factor, whereas CCL5 production required PI3/Akt and NFkB
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