STAT1 and STAT3 alpha/beta splice form activation predicts host responses in mouse hepatitis virus type 3 infection.
Signal transducer and activator of transcription 1alpha (STAT1 alpha) is reported to be essential for IFN-gamma and IFN-alpha regulated gene expression, while STAT1 beta, an alternate splice-form, mediates only IFN-alpha-dependent gene expression. STAT3 alpha and STAT3 beta splice forms are also differentially activated in response to cytokines including IL-6 and IL-10. The aim of this study was to investigate whether the STAT activation will predict the host immune response to viral infection and possibly a therapeutic target for the treatment of viral infection. Mouse hepatitis virus type 3 (MHV-3) resistant strain (A/J) and sensitive mouse strains (BalB/cJ) were infected intraperitoneally (i.p.) with 100 plaque form units (pfu) of MHV-3. The mice were sacrificed at the indicated times, and livers and spleens were immediately frozen in liquid nitrogen. Nuclear extracts proteins were detected by immunoblotting. STAT1 and STAT3 activation in spleen increased 24 to 72 hr following MHV-3 infections in both sensitive and resistant mouse strains. However, over this time period, the ratio of activated alpha to beta splice-form for STAT1 and STAT3 increased above 1.0 in resistant A/J mice, while the ratio fell to <0.3 in MHV-3 sensitive Balb/cJ and C3H/HeJ strains. Activated STAT1 alpha/beta and STAT3 alpha/beta ratio in liver were similar in resistant and sensitive mouse strains. Treatment of sensitive Balb/cJ mice with neutralizing anti-TGF-beta antibody could increase the STAT1 alpha/beta ratio to <1.0 in spleens, predicting enhanced rates of survival. These results suggested that ratio of activated STAT1 alpha/beta and STAT3 alpha/beta in mixed leukocytes from spleen predict the outcome to MHV-3 infection, and may be an important marker and therapeutic target for modification of host immune response to virus infection.
Ning
Qin
Q
Division of Clinical Immunology, Tongji Hospital, Institute of Immunology, Tongji Medical College and Huazhong University of Science and Technology, Wuhan, China. qning@tjh.tjmu.edu.cn
Berger
Lloyd
L
Luo
Xiaoping
X
Yan
Weiming
W
Gong
Feili
F
Dennis
James
J
Levy
Gary
G
D017398:Alternative Splicing; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006524:Hepatitis, Viral, Animal / Q000276:immunology* / Q000628:therapy; D008099:Liver / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D006517:Murine hepatitis virus / Q000276:immunology* / Q000472:pathogenicity; D011237:Predictive Value of Tests; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D013154:Spleen / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000276:immunology
D000906:Antibodies; D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta