CC chemokine receptor 5 gene promoter activation by the cyclic AMP response element binding transcription factor.
The chemokine receptor CCR5 is implicated in the pathogenesis of various inflammatory diseases, such as multiple sclerosis (MS), atherosclerosis, transplant rejection, and autoimmunity. In previous studies, we have shown that MS lesions are characterized by enhanced expression of transcription factors associated with stress responses, ie, IRF-1, NF-kappaB, and CREB-1, which modulate expression of both classes of major histocompatibility complex (MHC) molecules. The expression of MHC-I and MHC-II molecules greatly overlaps with the expression of CCR5 in MS lesions. Therefore, we investigated whether these factors are also involved in the transcriptional regulation of CCR5. Using in vitro assays, we determined that neither IRF-1 nor NF-kappaB is involved in the activation of the CCR5 promoter. This is corroborated by the finding that these factors are not involved in the induction of endogenous CCR5 transcription in various cell types. In contrast, we show that CCR5 expression is regulated by the cAMP/CREB pathway and that interference in this pathway affects endogenous CCR5 transcription. From this, we conclude that the cAMP/CREB pathway is involved in the regulation of CCR5 transcription and that, given the ubiquitous nature of CREB-1 protein expression, additional regulatory mechanisms must contribute to cell type-specific expression of CCR5.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, The Netherlands.
Hedwich F
HF
Kuipers
Paula J
PJ
Biesta
Lisette J
LJ
Montagne
Elise S
ES
van Haastert
Paul
P
van der Valk
Peter J
PJ
van den Elsen
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D017628:Microglia / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D012333:RNA, Messenger; D019713:Receptors, CCR5; D005576:Colforsin