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Rac1 Contributes to Maximal Activation of STAT1 and STAT3 in IFN--Stimulated Rat Astrocytes¹

Eun Jung Park^2,*, Kyung-Ae Ji^2,, Sae-Bom Jeon^,, Woo-Hyuck Choi, Inn-oc Han, Hye-Jin You^¶, Jae-Hong Kim^¶, Ilo Jou^* and Eun-Hye Joe^3,*,,

^* Department of Pharmacology, Department of Neuroscience, Brain Disease Research Center, School of Medicine, Ajou University, Suwon, Korea; Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea; and ^¶ School of Life Sciences and Biotechnology, Korea University, Seoul, Korea

Rac1 GTPase is implicated as a signaling mediator in various cellular events. In this study, we show that Rac1 contributes to IFN--induced inflammatory responses in rat astrocytes. We revealed that IFN- 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--responsive transcriptional responses. Compared with levels in control cells, IFN--induced IFN--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--responsive genes, such as MCP-1 and ICAM-1, was also reduced in cells expressing RacN17. Consistent with these observations, IFN--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-R subunit and IFN--induced phosphorylation of JAK1 between C6 control and C6-RacN17 cells. Interestingly, Rac1 appeared to associate with IFN-R and augment the interaction of IFN-R with either STAT1 or STAT3 in response to IFN-. Taken together, we suggest that Rac1 may serve as an auxiliary mediator of IFN--signaling, at least at the level of STAT activation, thus contributing to maximal activation of IFN--responsive inflammatory signaling in rat astrocytes.

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