HEPATOCYTE GROWTH FACTOR REGULATES INFLAMMATORY MEDIATED DISEASES BY SUPPRESSION OF IL-6: IMPLICATIONS FOR TYPE 2 DIABETES

The generation of the pro-inflammatory cytokines IL-6 and TNF-α by macrophages recruited to adipose tissue facilitates obesity-induced inflammation resulting in insulin resistance and type 2 diabetes (T2D). Increased adipose tissue is associated with inflammation and expression of acute phase response (APR) proteins secreted by the liver. Proper homeostasis of the liver is regulated by IL-6-depdendent expression of Hepatocyte Growth Factor (HGF) upon cleavage to its active form (aHGF) by the urokinase-type plasminogen activator (uPA). Plasminogen Activator Inhibitor Type-1 (PAI-1) is a pro-thrombotic APR protein known to inhibit the function of uPA; however, since HGF's activation, interaction and signaling through its receptor, MET are dependent upon uPA, PAI-1 is also capable of regulating the function of hepatic HGF. In vitro data demonstrates that aHGF significantly suppressed IL-6 production by macrophages stimulated with LPS via an increase in phosphorylation of GSK3β, rendering it inactive. Phosphorylated GSK3β correlated with increased retention of the phosphorylated NF-κB p65 subunit in the cytoplasm and an enhanced interaction between CBP and phosphorylated CREB resulting in IL-10 cytokine production. These changes were a direct result of signaling through MET, as effects were reversed in the presence of a selective inhibitor of MET (SU11274) or when using BMM from macrophage-specific conditional MET knockout mice.It is known that obese T2D patients present with an accumulation of PAI-1, which we hypothesize, results in the inactivation of HGF. The loss of HGF-MET signaling results in increased active GSK3β and the progression to unchecked inflammation and disease progression. In vivo studies using male, C57BL6 mice on a high fat diet alongside control fed mice demonstrates move severe hepatic steatosis in obese mice at 44 weeks compared to control. Steatosis coincided with the decrease in aHGF and elevated levels of PAI-1 protein. These results demonstrate that elevated levels of PAI-1 inhibit aHGF, leading to unresolved chronic inflammation in obesity and T2D