Z Gastroenterol 2012; 50 - A26
DOI: 10.1055/s-0032-1312380

Impaired STAT4 phosphorylation is associated with non-response to PEG-IFN plus Ribavirin treatment in chronic HCV Hepatitis patients

M Halasz 1, L Szereday 1, T Berki 2, L Pálinkás 2, A Vincze 3, A Pár 3, G Pár 3
  • 1Department of Medical Microbiology and Immunology, University of Pecs, Hungary
  • 2Department of Immunology and Biotechnology, University of Pecs, Hungary
  • 3First Department of Medicine, University of Pecs, Hungary

Background: The standard therapy for chronic hepatitis C (CHC) is combination of PEG- IFN and ribavirin that results sustained viral clearance in only half of HCV1 genotype patients. It is known that PEG-IFN induces upregulation of IFN-stimulated genes (ISG) transcription by activating the Jak-STAT pathway and promotes Th1 type cytokine production. While activated STAT4 regulates Th1 cell development, STAT6 is important in the activation of IL-4 and Th2 cytokine induction. Increased Th2 type cytokine production was associated with non-response to PEG-IFN. To investigate the underlying molecular mechanisms of non-response to PEG-IFN, we compared IFNalpha-induced STAT4/STAT6 signaling pathways in PEG-IFN responder and non-responder CHC patients.

Patients and methods: Twenty CHC patients and 10 healthy controls were enrolled. Peripheral blood mononuclear cells (PBMC) were separated and treated with PEG-IFNalpha2b in vitro. Lysates of PBMC were subjected to Western blotting to detect phosphorylated STAT4 and STAT6 transcription factors. Th1/Th2 cytokine production was also detected by CBA assay from the supernatants of the stimulated PBMC. We correlated the molecular data with the response to treatment.

Results: In CHC patients who responded to PEG-IFN treatment in vitro IFNalpha stimulation of PBMC resulted strong STAT4 phosphorylation and increased Th1 type cytokine production compared to controls and non-responders. IFNalpha induced phosphorylation of STAT4 that was reduced in non-responder group compared to controls. Th2 type cytokine production was increased in non-responder group. STAT6 transcription factor activation did not differ between study groups.

Conclusions: Favourable PEG-IFN/RBV treatment outcome was associated with an increased PEG-IFNalpha induced STAT4 phosphorylation. Defective JAK/STAT activation was associated with non-response to PEG-IFN/RBV therapy. The differences of IFNalpha induced signal transduction pathways between responder and non-responder group may provide a rationale for the further design and use of new therapeutic approches targeting the signal transduction pathways in HCV treatment.