Anti-inflammatory effects of hepatocyte growth factor on the vicious cycle of macrophages and adipocytes

Abstract

The paracrine loop involving inflammatory cytokines between adipocytes and macrophages establishes a vicious cycle that aggravates pro-inflammatory changes in adipose tissue. The serum level of hepatocyte growth factor (HGF) is increased in metabolic syndrome, but whether HGF is beneficial or detrimental in inflammatory conditions is unclear. We previously reported that HGF has strong anti-inflammatory effects. We therefore hypothesized that HGF may inhibit chronic inflammation in adipose tissue by inhibiting the vicious cycle between adipocytes and macrophages. We stimulated the macrophage cell line RAW264 with HGF and evaluated pro-inflammatory cytokines. Coculturing differentiated 3T3-L1 adipocytes with RAW264 results in marked upregulation of pro-inflammatory cytokines. We examined whether HGF suppresses the upregulation of pro-inflammatory cytokines in this coculture system. Cardiac-specific HGF transgenic mice (HGF-Tg) were crossed with ApoE KO (knockout) mice, to yield ApoE KO/HGF-Tg mice, which were treated with a high-fat diet (HFD) and received angiotensin (Ang) II. The phenotypes of ApoE KO and ApoE KO/HGF-Tg mice were compared. Treatment with HGF reduced the expression of pro-inflammatory cytokine genes (Tumor necrosis factor-α, monocyte chemoattractant protein-1 and interleukin-6) in RAW264 and the coculture system. The anti-inflammatory effects of HGF were also confirmed in in vivo studies. Macrophage infiltration in epididymal adipose and fatty liver was reduced in ApoE KO/HGF-Tg. Adipocyte diameter was reduced in ApoE KO/HGF-Tg, and the serum adiponectin level was upregulated. These beneficial effects in ApoE KO/HGF-Tg mice under HFD and Ang II infusion were abrogated by an anti-HGF neutralizing antibody. These results suggest that HGF inhibits the vicious cycle of adipocytes and macrophages through the inhibition of macrophage-mediated pro-inflammatory cytokines and upregulation of adiponectin in adipocytes. These favorable effects may suppress chronic inflammation in adipose tissue.