Rac1 contributes to maximal activation of STAT1 and STAT3 in IFN-gamma-stimulated rat astrocytes.
Rac1 GTPase is implicated as a signaling mediator in various cellular events. In this study, we show that Rac1 contributes to IFN-gamma-induced inflammatory responses in rat astrocytes. We revealed that IFN-gamma rapidly stimulated activation of Rac1 in C6 astroglioma cells by investigating GST-PAK-PBD-binding ability. We also found that Rac1 deficiency led to attenuation of IFN-gamma-responsive transcriptional responses. Compared with levels in control cells, IFN-gamma-induced IFN-gamma-activated sequence promoter activity was markedly reduced in both C6 astroglioma cells and primary astrocytes expressing RacN17, a well-characterized Rac1-negative mutant. The expression of several IFN-gamma-responsive genes, such as MCP-1 and ICAM-1, was also reduced in cells expressing RacN17. Consistent with these observations, IFN-gamma-induced phosphorylation of STAT1 and STAT3 was lower in C6 cells expressing RacN17 (referred to as C6-RacN17) than in control cells. However, there was no difference in expression level of IFN-gammaRalpha subunit and IFN-gamma-induced phosphorylation of JAK1 between C6 control and C6-RacN17 cells. Interestingly, Rac1 appeared to associate with IFN-gammaRalpha and augment the interaction of IFN-gammaR with either STAT1 or STAT3 in response to IFN-gamma. Taken together, we suggest that Rac1 may serve as an auxiliary mediator of IFN-gamma-signaling, at least at the level of STAT activation, thus contributing to maximal activation of IFN-gamma-responsive inflammatory signaling in rat astrocytes.
Park
Eun Jung
EJ
Department of Pharmacology, School of Medicine, Ajou University, Suwon, Korea.
Ji
Kyung-Ae
KA
Jeon
Sae-Bom
SB
Choi
Woo-Hyuck
WH
Han
Inn-Oc
IO
You
Hye-Jin
HJ
Kim
Jae-Hong
JH
Jou
Ilo
I
Joe
Eun-Hye
EH
D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D053613:Janus Kinase 1; D010766:Phosphorylation; D021122:Protein Subunits / Q000096:biosynthesis / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D053613:Janus Kinase 1; D021122:Protein Subunits; D011505:Protein-Tyrosine Kinases; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D020830:rac1 GTP-Binding Protein; D000096743:Interferon gamma Receptor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; C507906:Jak1 protein, rat