Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases

Abstract

The contribution of the acute phase inducer interleukin 6 (IL-6) in the pathogenesis of liver diseases is yet unclear. Our analysis showed enhanced expression of IL-6 in livers derived from patients with acute and chronic liver diseases. Additionally, IL-6 plasma levels were significantly increased in patients with chronic liver diseases and showed an inverse correlation with biochemical markers of liver function and a positive correlation with inflammatory markers, signs of portal hypertension, and the degree of liver fibrosis. To prove the relevance of these clinical findings, we applied the tetrachlorcarbonide (CCl 4 ) model to conditional knockout animals (Cre/loxP system) for gp130, the common signal transducer of IL-6 family cytokines. Cre recombinases were expressed through a hepatocyte (AlfpCre) and a ubiquitous (MxCre) control element. Gp130 deleted mice had a totally abolished STAT3 activation and acute phase response induction, but gp130 deletion had no effect on the degree of acute liver injury and subsequent hepatocyte proliferation. In contrast, during chronic liver injury induced by biweekly application of CCl 4 , deletion of the gp130 receptor in nonparenchymal liver cells and not hepatocytes resulted in fibrosis progression. In conclusion, our experiments indicate an involvement of IL-6 in the pathogenesis of liver diseases and suggest a protective role of IL-6/gp130-dependent pathways in nonparenchymal liver cells during fibrosis progression in chronic liver diseases. (HEPATOLOGY 2003;38:218-229.)

Pioglitazone promotes survival and prevents hepatic regeneration failure after partial hepatectomy in obese and diabetic KK-Ay mice

“…7A, B) and increased cyclin D1 expression after PH in KK-A y mice. Because the JAK-STAT pathway is involved in tissue protection in various kinds of hepatic injuries, 28,29 up-regulation of the JAK-STAT signaling in KK-A y mice is considered as a stress-related protective response in the liver. Importantly, it has been reported that excess phosphorylation of STAT3 results in poor hepatic regeneration because of direct down-regulation of cyclin D1 expression 26,30,31 and that higher SOCS-3 expression in hepatocytes lacking gp130-dependent Ras correlates with delayed hepatocyte proliferation.…”

Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver

“…To explore this possibility further at the transcriptional level, we determined the relative expression of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α, Fig. 4A), both of which have been implicated in oval and inflammatory responses in the liver (17)(18)(19)(20). For both IL-6 and TNF-α we observe modest, but significant increases in transcript level consistent with a generalized inflammatory and/or oval cell response (Fig.…”

Gp130 Signaling Promotes Development of Acute Experimental Colitis by Facilitating Early Neutrophil/Macrophage Recruitment and Activation

“…C57BL6/J mice carrying loxP sites flanking exon 16 coding for the gp130 transmembrane domain were crossed with transgenic (tg) mice expressing Cre-recombinase as described previously (16,17). Cre-recombinase expression was controlled by type I IFN-sensible Mx1 promotor (MxCre) (16).…”