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Published on: October 1, 2015
Undetectable phospho-STAT1 in peripheral blood mononuclear cells from patients with chronic hepatitis C who do not
Antonio Aceti1, Barbara Zechini, Tamara Griggi
1Department of Infectious Diseases, Sant'Andrea Hospital II, Faculty of Medicine, University of Rome La Sapienza, Via di Grottarossa 1035, 00189 Rome, Italy. professoraceti@tiscali.it
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-alpha 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.
Insights
Phosphorylated STAT1 (signal transducers and activators of transcription 1) is crucial for interferon (IFN) response in chronic hepatitis C. Undetectable levels in non-responders suggest a role in IFN sensitivity and treatment resistance.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Phosphorylated signal transducers and activators of transcription 1 (STAT1) is vital for interferon (IFN)-mediated antiviral functions.
- Suppressors of cytokine signaling 1 (SOCS1) negatively regulates IFN activity.
Purpose of the Study:
- To investigate the role of phospho-STAT1 in chronic hepatitis C patients undergoing IFN-alpha therapy.
- To evaluate SOCS1's negative regulatory effect on STAT1 activation.
Main Methods:
- Western blot analysis of total STAT1, phospho-STAT1, and SOCS1 in peripheral blood mononuclear cells (PBMCs).
- Study included 65 chronic hepatitis C patients (25 naive, 40 treated) and 25 healthy controls.
- PBMCs were stimulated with IFN-alpha or left unstimulated.
Main Results:
- Total STAT1 expression was consistent across all groups.
- Detectable phospho-STAT1 was observed in 100% of healthy controls and sustained responders (SRs), 96% of naive subjects, and 30% of non-responders (NRs).
- Undetectable phospho-STAT1 was found in 70% of NRs.
Conclusions:
- Undetectable phospho-STAT1 in 70% of chronic hepatitis C non-responders suggests its involvement in IFN sensitivity.
- SOCS1-induced down-regulation of the Jak-STAT pathway may contribute to IFN resistance.
