Identification of CXCL11 as a STAT3-dependent gene induced by IFN.
IFNs selectively regulate gene expression through several signaling pathways. The present study explored the involvement of STAT3 in the IFN-induced expression of the gene encoding the CXCL11 chemokine. The CXCL11 gene was induced in IFN-sensitive Daudi cells, but not in an IFN-resistant DRST3 subline with a defective STAT3 signaling pathway. Although the IFN-stimulated gene ISG15 was induced to a similar extent in Daudi and DRST3 cells, expression of wild-type STAT3 in DRST3 cells restored the IFN inducibility of CXCL11. Reconstitution of STAT3 knockout mouse embryonic fibroblasts with wild-type STAT3, or STAT3 with the canonical STAT3 dimerization site at Y705 mutated, restored IFN inducibility of the CXCL11 gene. These data indicate that CXCL11 gene induction by IFN is STAT3 dependent, but that phosphorylation of Y705 of STAT3 is not required. Chromatin immunoprecipitation assays demonstrated that IFN treatment of Daudi and DRST3 cells induced STAT3 binding to the CXCL11 promoter. Chromatin immunoprecipitation assays also revealed that NF-kappaB family member p65 and IFN regulatory factor (IRF)1 were bound to CXCL11 promoter upon IFN treatment of Daudi cells. In contrast, IFN induced the binding of p50 and IRF2 to the CXCL11 promoter in DRST3 cells. The profile of promoter binding was indistinguishable in IFN-sensitive Daudi cells and DRST3 cells reconstituted with wild-type STAT3. Thus, STAT3 also plays a role in the recruitment of the transcriptional activators p65 and IRF1, and the displacement of the transcriptional repressors p50 and IRF2 from the CXCL11 promoter also appears to regulate the induction of CXCL11 gene transcription.
Yang
Chuan He
CH
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Cancer Institute, Memphis, TN 38163, USA.
Wei
Lai
L
Pfeffer
Susan R
SR
Du
Ziyun
Z
Murti
Aruna
A
Valentine
William J
WJ
Zheng
Yi
Y
Pfeffer
Lawrence M
LM
D000818:Animals; D002460:Cell Line; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D007372:Interferons / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
D054371:Chemokine CXCL11; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; D050796:STAT3 Transcription Factor; D019000:Phosphotyrosine; D007372:Interferons