Transcriptional regulation of the major HIV-1 coreceptor, CXCR4, by the κ opioid receptor

Journal of Leukocyte Biology

William D. Cornwell and²  Thomas J. Rogers¹  Thomas J. Rogers ,3²  William D. Cornwell¹  *¹  Amber Steele ²  Matthew J. Finley¹  Amber Steele¹  Matthew J. Finley ² 

[1] Fels Institute for Cancer Research and Molecular Biology, Department of Pharmacology, and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA Fels Institute for Cancer Research and Molecular Biology, Fels Institute for Cancer Research and Molecular Biology, Department of Pharmacology, and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA Department of Pharmacology, and Fels Institute for Cancer Research and Molecular Biology, Department of Pharmacology, and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA Fels Institute for Cancer Research and Molecular Biology, Department of Pharmacology, and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA;Fels Institute for Cancer Research and Molecular Biology, Department of Pharmacology, and  Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

关键词: JAK;    STAT;    IRF;   

DOI  :  10.1189/jlb.1010546

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Previous studies have demonstrated that KOR activation results in decreased susceptibility to infection by HIV-1 in human PBMCs. In the present studies, we have found this effect is, in part, a result of down-regulation of the major HIV-1 coreceptor, CXCR4. Using a combination of biochemical approaches, our results show that CXCR4 protein and mRNA levels were reduced significantly following KOR activation. We evaluated the nature of the signaling pathway(s), which were induced by KOR activation, using transcription factor-binding array analysis and comparing extracts from control and KOR-activated cells. We determined that the IRFs and STATs were induced following KOR activation, and these events were important for the inhibition of CXCR4 expression. Using chemical inhibitors and siRNA constructs, we determined that JAK2, STAT3, and IRF2 were critical members of this signal transduction pathway. Immediately following KOR activation, JAK2 was phosphorylated, and this was required for the phosphorylation/activation of STAT3. Moreover, IRF2 mRNA and protein expression were also up-regulated, and further studies using ChIP analysis showed that IRF2 was induced to bind in vivo to the CXCR4 promoter. This is the first report detailing the initiation of a KOR-induced JAK2/STAT3 and IRF2 signaling cascade, and these pathways result in substantial down-regulation of CXCR4 expression. The capacity of KOR to down-regulate CXCR4 expression may provide a strategy for the development of novel therapeutics for the inhibition of HIV replication.

【 授权许可】

Unknown