Function of Mitogen-Activated Protein Kinases in Hepatic Inflammation

Abstract

The western diet and overuse of anti-inflammatory medication have caused a great deal of stress on the liver. Obesity and the associated inflammatory state in insulin-responsive tissues result in the release of pro-inflammatory cytokine that activates the stress-responsive MAPKs, p38 MAPK, and JNK. These MAPKs have figured prominently as critical effectors in physiological and pathophysiological hepatic inflammation. In contrast, evidence for a role for ERK1/2 in hepatic inflammation has been less well developed. In this review article, we describe recent insights into the physiology and pathophysiology of the role of stress-responsive MAPKs in hepatic inflammation during obesity and liver injury with a focus on macrophages, hepatocytes and hepatic stellate cells. In response to metabolic stress and liver injury, JNK activation in macrophages and hepatocytes promotes the secretion of inflammatory cytokines and macrophage and neutrophil infiltration. p38 MAPK plays an important role in contributing to the progression of hepatic inflammation in response to various hepatic cellular stresses, although the precise substrates mediating these effects in hepatocytes and hepatic stellate cells remain to be identified. Both JNK and p38 MAPK promotes profibrotic behavior in hepatic stellate cells.

Keywords: Hepatic inflammation; Liver injury; MAP kinase; Obesity.

Figure 1:. Model for MAPK regulation of inflammation in liver injury.

In macrophages (A); HFD activate JNK to promote M1 polarization and secretion of inflammatory cytokines whereas activation of p38 MAPK stimulate secretion of TNFα and steatohepatitis. In hepatic stellate cells (HSC) (B); proinflammatory cytokines activate JNK to stimulate TGF-β expression thereby promoting fibrosis. Interleukins activate p38 MAPK to induce secretion of extracellular matrix and differentiation of HSC to promote hepatic fibrosis. In hepatocytes (C); acetaminophen (APAP) injury activate JNK to stimulate production inflammatory cytokines, macrophage and neutrophil infiltration and formation of reactive oxygen species. HFD and acute liver injury activate p38 MAPK to stimulate hepatic lipid accumulation and inflammation.