Role of placental growth factor and its receptor Flt-1 in rheumatoid inflammation: A link between angiogenesis and inflammation

Objective. To investigate the direct effects of placenta growth factor (PIGF) and its specific receptor, flt-1, which are known to mediate angiogenesis, on the inflammatory process of rheumatoid arthritis (RA). Methods. Expression of PIGF 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 PIGF, tumor necrosis factor alpha (TNF alpha), 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. PIGF was highly expressed in the synovium of RA patients, and its primary source was fibroblast-like synoviocytes (FLS). When stimulated with 1L-1 beta, FLS from RA patients produced higher amounts of PIGF than did FLS from patients with osteoarthritis. Exogenous PIGF specifically increased the production of TNF alpha and IL-6 in mononuclear cells from RA patients (but not those from healthy controls) via a calcineurin-dependent pathway. The response to PIGF was associated with increased expression of flt-1 on RA monocytes, which could be induced by IL-1 beta and TNFa. A novel anti-flt-1 hexapeptide, GNQWFI, abrogated the PIGF-induced increase in TNFa and IL-6 production, and also suppressed CII-induced arthritis and serum IL-6 concentrations in mice. Moreover, genetic ablation of PIGF prevented the development of anti-CII antibody-induced arthritis in mice. Conclusion. Our data suggest that enhanced expression of PIGF 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.