Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: a link between angiogenesis and inflammation.

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.

• Authors: Seung-Ah Yoo, Hyung-Ju Yoon, Hyun-Sook Kim, Chi-Bom Chae, Sandro De Falco, Chul-Soo Cho, Wan-Uk Kim
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 60 Issue 2 Pg. 345-54 (Feb 2009) ISSN: 0004-3591 [Print] United States
• PMID: 19180491 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IL6 protein, human
• Interleukin-1beta
• Interleukin-6
• Oligopeptides
• PGF protein, human
• Pgf protein, mouse
• Pregnancy Proteins
• Tumor Necrosis Factor-alpha
• Placenta Growth Factor
• FLT1 protein, human
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Arthritis, Experimental (metabolism)
• Arthritis, Rheumatoid (metabolism, pathology, physiopathology)
• Cells, Cultured
• Disease Models, Animal
• Female
• Fibroblasts (drug effects, metabolism, pathology)
• Gene Silencing
• Humans
• Inflammation (metabolism)
• Interleukin-1beta (pharmacology)
• Interleukin-6 (metabolism)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Knockout
• Middle Aged
• Neovascularization, Pathologic (metabolism)
• Oligopeptides (pharmacology)
• Osteoarthritis (metabolism, pathology)
• Placenta Growth Factor
• Pregnancy Proteins (genetics, metabolism, pharmacology)
• Synovial Membrane (pathology)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)
• Vascular Endothelial Growth Factor Receptor-1 (metabolism)