Differential Gene Expression Downstream of Toll-like Receptors (TLRs) ROLE OF c-Src AND ACTIVATING TRANSCRIPTION FACTOR 3 (ATF3)

作者：Nguyen Thuy Thanh; Johnsen Ingvild B; Knetter Cathrine F; Drablos Finn; Fitzgerald Katherine A; Lien Egil; Anthonsen Marit W^*

来源：Journal of Biological Chemistry, 2010, 285(22): 17011-17019.

DOI：10.1074/jbc.M109.068817

Interferon regulatory factors (IRFs) are crucial for transcription during innate immune responses. We have previously shown that the tyrosine kinase c-Src enhances IRF-3-dependent transcription in response to viral double-stranded RNA. In this study, we show that c-Src has distinct roles in Toll-like receptor (TLR)-mediated activation of IRF-5 and IRF-3. Surprisingly, c-Src inhibition markedly enhanced IRF-5 activation after treatment with unmethylated CpG, while suppressing IRF-3 activation. Also, CpG-elicited interleukin-6 mRNA production was increased, whereas IP10 mRNA synthesis was reduced in cells deficient in c-Src. Interestingly, c-Src regulated TLR-stimulated induction of activating transcription factor 3 (ATF3), a transcriptional repressor. Depletion of ATF3 by small interfering RNA markedly enhanced interleukin-6 production after CpG treatment, whereas IP10 production was reduced. These results demonstrate functional specificity for c-Src in TLR-stimulated responses and suggest that c-Src modulation and ATF3 activity may contribute to differential regulation of IRF-3-versus IRF-5-mediated gene expression.

• 出版日期2010-5-28