Role of IL-17 and Th17 Cells in Liver Diseases

Abstract

Unbalanced Th1/Th2 T-cell responses in the liver are a characteristic of hepatic inflammation and subsequent liver fibrosis. The recently discovered Th17 cells, a subtype of CD4+ T-helper cells mainly producing IL-17 and IL-22, have initially been linked to host defense against infections and to autoimmunity. Their preferred differentiation upon TGFβ and IL-6, two cytokines abundantly present in injured liver, makes a contribution of Th17 cells to hepatic inflammation very likely. Indeed, initial studies in humans revealed activated Th17 cells and Th17-related cytokines in various liver diseases. However, functional experiments in mouse models are not fully conclusive at present, and the pathogenic contribution of Th17 cells to liver inflammation might vary upon the disease etiology, for example, between infectious and autoimmune disorders. Understanding the chemokines and chemokine receptors promoting hepatic Th17 cell recruitment (possibly CCR6 or CCR4) might reveal new therapeutic targets interfering with Th17 migration or differentiation in liver disease.

The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

“…CCN2 has been involved in several chronic diseases, including skin disorders, cardiac hypertrophy, atherosclerosis, pulmonary hypertension, and lung and liver diseases, 12 where IL-17A is a key player. 32,33,[55][56][57][58] In the nonimmune murine model of UUO, we have observed elevated renal levels of IL-17A and infiltrating inflammatory cells associated with renal CCN2 overexpression. Although future studies are needed, our data showing that IL-17A blockade ameliorated CCN2-induced renal inflammation support the concept of CCN2 module IV regulates IL17A production R Rodrigues-Díez et al IL-17A-neutralizing antibody as a promising tool for chronic inflammatory diseases, including chronic kidney diseases.…”

Human Th17 Cells Express High Levels of Enzymatically Active Dipeptidylpeptidase IV (CD26)

“…Th17 cells are implicated in the pathogenesis of several inflammatory autoimmune diseases, including inflammatory bowel disease, autoimmune hepatitis, primary biliary cirrhosis, and viral hepatitis (26,27). To address whether IL-17-producing T cells in human diseases are also characterized by high levels of CD26 expression, we analyzed tissue specimen from diagnostic biopsies obtained from patients with active inflammatory bowel disease (Crohn's disease and ulcerative colitis), autoimmune hepatitis, primary biliary cirrhosis, and viral hepatitis.…”

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

“…IL-17A is produced by specific CD4 + Th cells (Th17) with proinflammatory properties that differ from Th1 and Th2 cells in development and function. Differentiation of Th17 cells requires the combined action of IL-1b, TGFb, IL-6, and IL-23 (6,7). These cytokines, which are induced by activated Kupffer and other cells, promote the expression of the lineage-specific transcription factor orphan nuclear receptor retinoic acid receptor gt (RORgt; in mice) or RORc (in humans), which is necessary and sufficient for the development of Th17 cells.…”

“…These cytokines, which are induced by activated Kupffer and other cells, promote the expression of the lineage-specific transcription factor orphan nuclear receptor retinoic acid receptor gt (RORgt; in mice) or RORc (in humans), which is necessary and sufficient for the development of Th17 cells. IL-17A plays a critical role in neutrophil recruitment, angiogenesis, inflammation, and autoimmune disease that has been previously described extensively (6), including in pulmonary and cardiac fibrosis via IL-17RA and MAPK signaling (8,9). However, very few studies have investigated the role of IL-17A in liver fibrosis (10).…”