Differential gene expression downstream of Toll-like receptors (TLRs): role of c-Src and activating transcription factor 3 (ATF3).
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.
Nguyen
Thuy Thanh
TT
Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, N-7006 Trondheim, Norway.
Johnsen
Ingvild B
IB
Knetter
Cathrine F
CF
Drabløs
Finn
F
Fitzgerald
Katherine A
KA
Lien
Egil
E
Anthonsen
Marit W
MW
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D018899:CpG Islands; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D019061:src-Family Kinases
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C494232:IRF3 protein, human; C431713:IRF5 protein, human; D050838:Interferon Regulatory Factor-3; D050835:Interferon Regulatory Factors; D015850:Interleukin-6; C494233:Irf3 protein, mouse; C498178:Irf5 protein, mouse; D051193:Toll-Like Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human