Chronic alcohol consumption accelerates liver injury in T cell-mediated hepatitis: alcohol disregulation of NF-κB and STAT3 signaling pathways

Abstract

Alcohol consumption is a major risk factor accelerating the progression of liver disease in patients with chronic hepatitis virus infection. However, the mechanism underlying the enhanced susceptibility of alcoholics to liver injury is not fully understood. Here, we demonstrate that chronic ethanol consumption increases the susceptibility of C57BL/6 mice to concanavalin A (Con A)-induced T cell-mediated hepatitis. Injection of a low dose of Con A (5 microg/g) causes severe liver damage in ethanol-fed mice as evidenced by a significant elevation of serum alanine aminotransaminase levels, massive necrosis, and infiltration of leukocytes but only slightly induces liver injury in control pair-fed mice. In ethanol-fed mice, the activation and cytotoxicity of natural killer T cells, cells that play key roles in Con A-induced T cell hepatitis, are not significantly enhanced relative to pair-fed mice. Moreover, Con A-induced activation of hepatic NF-kappaB is increased, whereas activation of STAT1 and STAT3 is attenuated in ethanol-fed mice. Consistent with this result, the expression of chemokines and adhesion molecules [such as ICAM-1, macrophage inflammatory protein (MIP)-1, MIP-2, and MCP-1] controlled by NF-kappaB is upregulated, whereas STAT1-controlled expression of chemokines (such as MIG and IP-10) is downregulated in ethanol-fed mice compared with pair-fed mice. In conclusion, chronic alcohol consumption accelerates T cell-mediated hepatitis via upregulation of the NF-kappaB signaling pathway and subsequently enhances expression of chemokines/adhesive molecules and recruitment of leukocytes into the liver. Downregulation of the antiapoptotic STAT3 signal may also contribute to alcohol potentiation of T cell hepatitis.

Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling

“…It is also known that the NFB and MAPK pathways, including p38 and JNK, participate in HSC activation [45,46,47]. Therefore, we treatment of rats, and ongoing production of proinflammatory cytokines regulated by NFB is believed to play a major role in CCl 4 -induced liver fibrosis [48,49,50]. The key feature of liver fibrosis is the increase in collagen type I synthesis.…”

Inhibition of Immune-Mediated Concanavalin A-Induced Liver Damage by Free-Radical Scavengers

“…Several studies have demonstrated an essential role for NF-jb activation in Con A-induced hepatitis [44][45][46][47].…”

Antigen-presenting cells under the influence of alcohol

“…increased maturation, cytokine and chemokine secretion) [15,16]. Also, in mice, and in cell culture systems, alcohol affects other cell signaling pathways, such as reduced activation of signal transducer and activator of transcription (STAT)1 and STAT3 [17,18]. Furthermore, products of alcohol metabolism have been linked to autoimmunity (e.g.…”