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.
Highlights
In homeostasis, the liver is exerting various metabolic functions, and serves as a central “immunological” organ
It is well known that innate immune cells are important triggers of hepatic inflammation, because the liver is selectively enriched in macrophages (Kupffer cells), natural killer (NK), and natural killer T (NKT) cells [1]
Perpetuated inflammation and subsequent hepatic fibrosis are common characteristics of chronic liver diseases in humans and have long been thought to be primarily associated with unbalanced Th1/Th2 responses in the liver. This current view may have to be revised in some aspects since the recently discovered Th17 cells may play an active role in shaping the local inflammatory response in the liver
Summary
The liver is exerting various metabolic functions, and serves as a central “immunological” organ. Immune cells that reside in or travel through the liver have the potential to initiate either (a) innate and adaptive immune responses in case of infections, for example, in response to lipopolysaccharide (LPS) or bacterial superantigens or (b) immunological tolerance to the vast majority of harmless antigens during homeostasis [1]. Following liver injury, induced, for example, by hepatitis viruses, alcohol abuse, or nonalcoholic steatohepatitis, inflammation is a pathological hallmark feature of chronic liver diseases. The infiltration of monocytes upon liver injury is an important cellular mechanism to perpetuate chronic inflammation and to activate profibrogenic hepatic stellate cells (HSC) in mice and men [3, 4]. During conditions of chronic liver damage, adaptive immune cells are crucially involved in the pathogenesis of hepatic inflammation. This paper will present the concept of different CD4+ T-helper cell subsets and summarize their proposed functions during liver diseases, with a focus on the current knowledge about the role of Th17 cells and their associated cytokines in liver inflammation in mice and men
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