Undetectable phospho-STAT1 in peripheral blood mononuclear cells from patients with chronic hepatitis C who do not respond to interferon-α therapy

Background: Recent studies have suggested that phosphorylated signal transducers and activators of transcription 1 (STAT1) plays an important role in interferon (IFN)-mediated biological functions, including antiviral activity. Moreover, it has been demonstrated that suppressors of the cytokine signal 1 (SOCS1) negatively regulates IFN activities. Aims: To investigate the involvement of phospho-STAT1 in the response to IFN-alpha therapy in patients with chronic hepatitis C and to evaluate the negative regulatory effect of SOCS1 on STAT1 activation. Methods: Sixty-five patients with chronic hepatitis C and 25 healthy subjects were enrolled. Twenty-five of the patients had never been treated with IFN-a therapy (naive), while the remaining 40 patients had. The IFN-treated patients were divided into sustained responders (SRs) or non-responders (NRs) on the basis of their response to the antiviral therapy. Peripheral blood mononuclear cells (PBMCs) were obtained from each patient and control, and were either stimulated with IFN-alpha or left unstimulated. Total STAT1, phospho-STAT1 and SOCS1 were revealed by means of Western blot. Results: Total STAT1 was equally expressed in unstimulated and stimulated PBMCs from all patients and controls. One hundred percent of the stimulated PBMCs from healthy controls and SRs, 96% from naive subjects, and 30% from NRs showed detectable phospho-STAT1. By contrast, 70% of the stimulated PBMCs from NRs showed undetectable phospho-STAT1. Conclusions: We have demonstrated that phospho-STAT1 proteins in 70% of patients with chronic hepatitis C who do not respond to IFN treatment are undetectable, which suggests that this protein may be involved in the mediation of IFN sensitivity. The down-regulation of the Jak-STAT pathway because of SOCS1 expression may be one of the possible underlying mechanisms involved in resistance to IFN.