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


OBJECTIVE
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.
Aceti
Antonio
A
Department 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
Zechini
Barbara
B
Griggi
Tamara
T
Marangi
Massimo
M
Pasquazzi
Caterina
C
Quaranta
Giorgio
G
Sorice
Maurizio
M
D000328:Adult; D000368:Aged; D024882:Drug Resistance, Viral; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000737:chemistry*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D012097:Repressor Proteins / Q000097:blood; D050794:STAT1 Transcription Factor / Q000097:blood*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000097:blood
D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins