Open AccessRole of placenta growth factor and its receptor flt‐1 in rheumatoid inflammation: A link between angiogenesis and inflammation
Author(s) -
Yoo SeungAh,
Yoon HyungJu,
Kim HyunSook,
Chae ChiBom,
De Falco Sandro,
Cho ChulSoo,
Kim WanUk
Publication year - 2009
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.24289
Subject(s) - medicine , angiogenesis , inflammation , tumor necrosis factor alpha , arthritis , peripheral blood mononuclear cell , rheumatoid arthritis , placental growth factor , immunology , cytokine , endocrinology , vascular endothelial growth factor , biology , biochemistry , in vitro , vegf receptors
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 α (TNFα), 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‐1β, FLS from RA patients produced higher amounts of PlGF than did FLS from patients with osteoarthritis. Exogenous PlGF specifically increased the production of TNFα 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‐1β and TNFα. A novel anti–flt‐1 hexapeptide, GNQWFI, abrogated the PlGF‐induced increase in TNFα 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.