Improvement of Sepsis by Hepatocyte Growth Factor, an Anti-Inflammatory Regulator: Emerging Insights and Therapeutic Potential

Figure 3

Molecular mechanisms of HGF-c-Met-mediated signaling for inhibiting TLR4-mediated NF-κB activation in macrophages. (a) HO-1-dependent pathway. HO-1 is upregulated at a downstream of TLR4 through the activation of transcriptional factors, such as Nrf2 or HIF-1. During heme metabolism by HO-1, carbon monoxide (CO), free iron and biliverdin are generated, and these products attenuate NF-κB activation (i.e., negative feedback system). In this process, c-Met signal enhances the HO-1 transcriptional pathway (1a) or stabilizes HO-1 from degradation (1b). Overall, HGF-mediated increases in HO-1 partially contribute to NF-κB inactivation (1c). (b) GSK3β-inactivated pathway. LPS-TLR4-mediated signaling leads to nuclear localization and activation of NF-κB via GSK3β activation pathway. In contrast, HGF-c-Met signaling elicits PI3K and AKT phosphorylation, and then GSK3β is inactivated. As a result, CBP, a coactivator of NF-κB, is sequestered from the p65 subunit of NF-κB, and transcription of inflammatory molecules, such as TNF-α, IL-6 and ICAM-1, is arrested.