Essential Role of STAT3 in the Control of the Acute-Phase Response as Revealed by Inducible Gene Activation in the Liver

Abstract

We generated mice carrying a STAT3 allele amenable to Cre-mediated deletion and intercrossed them with Mx-Cre transgenic mice, in which the expression of Cre recombinase can be induced by type I interferon. Interferon-induced deletion of STAT3 occurred very efficiently (more than 90%) in the liver and slightly less efficiently (about 70%) in the bone marrow. Analysis of the induction of liver acute-phase genes in response to bacterial lipopolysaccharide unequivocally identifies STAT3 as a fundamental mediator of their induction. The different degrees of defectiveness displayed by the various genes allowed us to differentiate them into three separate groups according to their degree of dependence on STAT3. Induction was totally defective for group I genes, defective at 24 h but almost normal at earlier time points for group II genes, and only slightly defective for group III genes. This division was in good agreement with the known structures of the respective promoters. We also found that the overall induction of the transcription factors C/EBP beta and -delta was only minimally defective in the absence of STAT3. Finally, even though corticosterone levels and action were found to be normal in the conditional-mutant mice, production of both proinflammatory and antiinflammatory cytokines was increased and prolonged, probably as a result of STAT3 deletion in macrophages.

Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice

“…It has been established that STAT3 regulates the expression of most, if not all, APPs in the liver. 19 Consistent with this, L-STAT3 KO mice displayed impaired production of APPs in response to CLP (Fig. 2B).…”

“…CLP activated liver STAT1 both in L-STAT3 KO mice and wild-type mice, suggesting that the absence of STAT3 does not affect the activation of other STATs. Given that STAT3 is a wellknown mediator for APP, 19 we measured APPs such as fibrinogen and haptoglobin in plasma after CLP (Fig. 2B).…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…Acute-phase response is impaired in both IL-6 and STAT3-deficient animals. It is most likely that the L −/− STAT3 mice failed to survive because there was a disturbance in the acute-phase response, which is fundamentally dependent on STAT3 activation [66]. Another cytokine, IL-22 induced phosphorylation of STAT3 on a serine residue and has been shown to induce acute phase genes in the liver [67], an effect that has been described to be regulated by IL-6 mainly through STAT3 activation.…”

Signal Transduction in the Liver: C/Ebpβ Modulates Cell Proliferation and Survival

“…41 Analogously, the ratio of C/EBP␤:LIP may affect hepatocyte proliferation and differentiation, because it changes during liver development 40 and in LPS-mediated acute-phase response. 39 After the administration of LPS or partial hepatectomy, there is an increase in the nuclear expression of C/EBP␤ and of the transcriptional repressor LIP (C/EBP␤ 21 kd), 42,43 which may be physiologically relevant for liver regeneration induced by hepatectomy and acute phase reaction induced by LPS. LPS up-regulates mainly the translation from the fifth AUG codon of C/EBP␣ mRNA and the third AUG codon of the C/EBP␤ mRNA.…”