4 Short-term/acute ethanol exposure increases IL-10 expression by monocytes in human subjects, as well as in mice in response to LPS. When human subjects consume a single dose of alcohol, the production of IL-10 by isolated monocytes in response to LPS is increased compared with controls.25 This increase can be prevented by inhibiting HO-1 by pretreatment with zinc protoporphyrin.26 Taken together with the current data, it appears that although chronic

ethanol exposure decreases circulating concentrations of IL-10,4 both short-term/acute and chronic ethanol exposure contribute to an enhanced IL-10 expression PLX4032 in vivo in monocytes/macrophages in response to immunoregulatory signals, such as LPS or gAcrp. Dabrafenib datasheet IL-10 binds to a heterodimeric IL-10R, which undergoes transphosphorylation and then activates the Janus kinase/signal transducer and activator of transcription protein 3 (STAT3) pathway.27 Activation of STAT3 is essential for IL-10–dependent signaling.2 Chronic ethanol feeding increased IL-10–stimulated phosphorylation of JAK1 and STAT3 in

Kupffer cells. Furthermore, inhibition of STAT3 signaling through chemical inhibitors or through siRNA knockdown ameliorated IL-10–dependent expression of HO-1 (Fig. 6). Reports in the literature suggest that the impact of chronic ethanol on the regulation of STAT3 is complex and is likely to have ligand-specific and cell-type–specific effects. Exposure of primary cultures of hepatocytes to ethanol suppresses IL-6–stimulated STAT3 activation.28 Horiguchi and colleagues have identified cell specific roles for STAT3 in hepatocytes

compared with monocytes/macrophages in the liver.29 Expression of STAT3 in hepatocytes had a negative impact on liver injury and promoted inflammation, whereas expression of STAT3 in monocytes/macrophages suppressed inflammation during ethanol exposure.29 The anti-inflammatory role of STAT3 in monocytes/macrophages during chronic ethanol exposure is consistent with our identification of a critical contribution of STAT3 in Kupffer cells in mediating the anti-inflammatory effects MCE公司 of gAcrp. Accumulating evidence suggests that HO-1 plays an important anti-inflammatory role in chronic inflammatory diseases and protects cells from oxidative insult.15 Heme oxygenase catalyzes the initial and rate-limiting step in oxidative degradation of heme, yielding equimolar amounts of biliverdin IXα, carbon monoxide, and free iron.30 There are three isoforms of HO: HO-2 and HO-3 are constitutive forms, whereas HO-1 (also known as heat shock protein 32) is an inducible isozyme, with high expression levels in spleen and Kupffer cells.31 HO-1 is a stress-responsive protein whose expression is up-regulated by a broad spectrum of inducers, including heme, heavy metals, nephrotoxins, cytokines, endotoxins, and oxidative stress.