Cross-talk between IFN-α and TGF-β₁signaling pathways in preneoplastic rat liver

Abstract

Interferon-gamma/transforming growth factor-beta (IFN-gamma/TGF-beta) pathways have opposite effects on diverse cellular functions. However, little is known about interactions between IFN-alpha/TGF-beta. In previous studies, we showed that IFN-alpha2b increases TGF-beta(1) production and secretion in hepatocytes from preneoplastic rat livers. Here, the interaction between IFN-alpha/TGF-beta(1) pathways was explored. We observed a positive cross-talk between IFN-alpha and TGF-beta(1) signaling, with activation of both pathways. p300 protein levels in hepatocytes from preneoplastic livers were enough to interact with both activated Stat1 and Smad2/3. Besides, Smad7 was not directly related with TGF-beta(1) and IFN-alpha signals. Interestingly, we reported the novel finding that the autocrine TGF-beta(1) up-regulates TGF-betaRII at protein and mRNA levels. In conclusion, the intracellular signals triggered by IFN-alpha2b and by autocrine TGF-beta(1) are integrated at the nuclear level, where activated Stat1 and Smad2/3 are capable of interact with p300, present in no restrictive cellular amounts.

A Genetic Screen Identifies Interferon-α Effector Genes Required to Suppress Hepatitis C Virus Replication

“…Interestingly, an informatics analysis also found components of the PPARα/RXRα activation pathway (HSP90AA1, HSP90AB1, MAP2K4, PDIP1, TGFBR1, SMAD3) to be enriched in the HCV-IEGs detected in this screen (p= 9.11E-04). Detection of both TGFBR1 and SMAD3 as HCV-IEGs supports recent findings of positive crosstalk between the IFN-α and TGF-β signaling pathways 30 . Moreover, PDIP1 has been recognized as an ISG in multiple cell types, interacts with the interferon stimulated protein, ISG15, and has recently been implicated in autoimmune disease, but its role in viral infection is unclear 5, 13, 14, 17 .…”

Interferon-α2b and transforming growth factor-β1 treatments on HCC cell lines: Are Wnt/β-catenin pathway and Smads signaling connected in hepatocellular carcinoma?

“…We demonstrated that not only this pathway is activated in preneoplastic rat livers, but more important, that in vivo IFN-a2b treatment inhibits it [27]. Besides, we also showed an apoptotic effect of IFN-a2b on preneoplastic foci which was induced by oxidative stress and TGF-b1 release [28][29][30].…”

Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis

“…TGF-β has long been recognised as a key mediator of fibrosis in SSc 10. In a previous study, IFN-α2b increased TGF-β1 production and secretion in hepatocytes, suggesting a positive cross-talk between IFN and TGF-β signalling through smad2/3 activation 11. Among IFN signalling pathways, interferon regulatory factors (IRFs) are best characterised as transcriptional regulators of type I IFNs and IFN-inducible genes and play a pivotal role in the regulation of many facets of the innate and adaptive immune response 12.…”