| Research Abstract |
1)Prevention of leukocyte infiltration by HGF in ischemic renal tissues :
We previously demonstrated that HGF prevents the chronic allograft rejection in a rodent model of experimentalrenal transplantation, associated with the suppressed leukocyte infiltration. Based on the background, we investigated the molecularmechanisms whereby HGF suppressed intra-renalinfiltration of leukocytes. Using a murine model of renal ischemia, we show that HGF is a natural ligand to inhibit endothelial injuries and neutrophil extravasation. In mice after renal I/R, plasma HGF levels increased, along with c-Met/HGF receptor phosphorylation in the vascular endothelium. However, this c-Met activation was transient, associated with a decrease in endogenous HGF level, followed by neutrophil infiltration and renal dysfunction. Suppression of endothelial c-Met phosphorylation by anti-HGF IgG led to rapid progressions of neutrophil extravasation, tubular apoptosis and renal dysfunction. Inversely, enhancement of
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the c-Met activation by exogenous HGF blocked endothelial/tubular apoptotic injuries and acute renal failure. In this process, HGF prevented endothelial NF-κB activation and inhibited induction of an adhesion molecule (ICAM-1), resulting in attenuated vascular edema and neutrophil infiltration. Thus, we conclude that : 1)the HGF/c-Met system of endothelial cells confers an initial barrier to block neutrophil infiltration ; and 2)transient and insufficient HGF production allows for manifestation of post-ischemic renal failure. Our study provides a rationale as to why HGF supplementation elicits therapeutic effects in ischemic kidneys.
2)Inhibitory effect of HGF on T-lymphocyte activation and proliferation :
Next, we addressed whether HGF directly modulates immune responses in the activated T-lymphocytes. We injected muscle-derived myosin into rats to elicitauto-immune cardimyotitis. In the rat model, cardiac destruction and dysfunction developed, along with the infiltration of CD4+,- T-lymphocytes, in which some lymphocytes expressed c-Met/HGF receptor. When HGF cDNA was administrated into the diseased heart via an HVJ-liposome, T-cell infiltration was suppressed, leading to improvement in the cardimyotitis. In a primary culture system of T-lymphocytes, HGF directly suppressed proliferation and interferon production in the T-cell population, in response to the myosin. Such in vitro and in vivo studies identified HGF as a direct negative regulator if immunological challenges. Less
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