Hepatoprotection via the IL-6/Stat3 pathway

Abstract

Stat3 is a vital transcription factor that is activated downstream of the gp130 receptor, primarily via IL-6 signaling in adult liver. A new study demonstrates that Stat3 provides hepatoprotection against Fas-mediated apoptotic liver damage by two mechanisms: direct inactivation of caspases and reduction of reactive oxygen species.

Figure 1

Model for IL-6/Stat3 signaling pathway. IL-6 binds to its soluble receptor, sIL-6r, which binds to the gp130 receptor, resulting in the activation of Janus kinase (JAK). This leads to activation of the MAPK pathway and activation of Stat3 by tyrosine (Y) phosphorylation. Dimerized Stat3 is able to translocate into the nucleus and activate gene transcription. In the liver, this process promotes liver regeneration, the acute-phase response, and hepatoprotection against Fas and toxic damage. P, phosphate.

Figure 2

Proposed model for the actions of IL-6 and Stat3 that result in hepatoprotection against Fas activation. Interaction of FasL with its receptor activates the caspase cascade that is blocked by IL-6 and Stat3 through the upregulation of FLIP, Bcl-2, and Bcl-XL. Fas activation also generates an oxidative stimulus that is blocked by the upregulation of Ref-1. FADD, Fas-associated death domain; Rac1, RAS-related C3 botulinum toxin substrate 1; Apaf1, apoptotic protease activating factor; Bax, Bcl2-associated X protein; Bid, BH3-interacting domain death agonist.