1. Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: a link between angiogenesis and inflammation.
- Author
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Yoo SA, Yoon HJ, Kim HS, Chae CB, De Falco S, Cho CS, and Kim WU
- Subjects
- Animals, Arthritis, Rheumatoid pathology, Arthritis, Rheumatoid physiopathology, Cells, Cultured, Disease Models, Animal, Female, Fibroblasts drug effects, Fibroblasts metabolism, Fibroblasts pathology, Gene Silencing, Humans, Interleukin-1beta pharmacology, Interleukin-6 metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Middle Aged, Oligopeptides pharmacology, Osteoarthritis metabolism, Osteoarthritis pathology, Placenta Growth Factor, Pregnancy Proteins genetics, Pregnancy Proteins pharmacology, Synovial Membrane pathology, Tumor Necrosis Factor-alpha metabolism, Tumor Necrosis Factor-alpha pharmacology, Arthritis, Experimental metabolism, Arthritis, Rheumatoid metabolism, Inflammation metabolism, Neovascularization, Pathologic metabolism, Pregnancy Proteins metabolism, Vascular Endothelial Growth Factor Receptor-1 metabolism
- Abstract
Objective: To investigate the direct effects of placenta growth factor (PlGF) and its specific receptor, flt-1, which are known to mediate angiogenesis, on the inflammatory process of rheumatoid arthritis (RA)., Methods: Expression of PlGF and flt-1 in the synovial tissue of RA patients was examined using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the concentrations of PlGF, tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) in culture supernatants of either mononuclear cells or synoviocytes. The flt-1 expression level in mononuclear cells was analyzed by flow cytometry. Experimental arthritis was induced in mice either by immunization with type II collagen (CII) or by injection of anti-CII antibody., Results: PlGF was highly expressed in the synovium of RA patients, and its primary source was fibroblast-like synoviocytes (FLS). When stimulated with IL-1beta, FLS from RA patients produced higher amounts of PlGF than did FLS from patients with osteoarthritis. Exogenous PlGF specifically increased the production of TNFalpha and IL-6 in mononuclear cells from RA patients (but not those from healthy controls) via a calcineurin-dependent pathway. The response to PlGF was associated with increased expression of flt-1 on RA monocytes, which could be induced by IL-1beta and TNFalpha. A novel anti-flt-1 hexapeptide, GNQWFI, abrogated the PlGF-induced increase in TNFalpha and IL-6 production, and also suppressed CII-induced arthritis and serum IL-6 concentrations in mice. Moreover, genetic ablation of PlGF prevented the development of anti-CII antibody-induced arthritis in mice., Conclusion: Our data suggest that enhanced expression of PlGF and flt-1 may contribute to rheumatoid inflammation by triggering production of proinflammatory cytokines. The use of the novel anti-flt-1 peptide, GNQWFI, may be an effective strategy for the treatment of RA.
- Published
- 2009
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