title: Regulation of B7.1 costimulatory molecule is mediated by the IFN regulatory factor-7 through the activation of JNK in lipopolysaccharide-stimulated human monocytic cells.
abstract: The engagement of CD28 or CTLA-4 with B7.1 provides the essential second costimulatory signal that regulates the development of immune responses, including T cell activation, differentiation, and induction of peripheral tolerance. The signaling molecules and the transcription factors involved in B7.1 regulation are poorly understood. In this study we investigated the role of MAPKs in the regulation of LPS-induced B7.1 expression in human monocytes and the promonocytic THP-1 cells. Our results show that LPS-induced B7.1 expression in monocytic cells did not involve the activation of either p38 or ERKs. Using the JNK-specific inhibitor SP600125, small interfering RNAs specific for JNK1 and JNK2, and agents such as dexamethasone that inhibit JNK activation, we determined that LPS-induced B7.1 expression was regulated by JNK MAPK in both monocytes and THP-1 cells. In addition, we identified a distinct B7.1-responsive element corresponding to the IFN regulatory factor-7 (IRF-7) binding site in the B7.1 promoter responsible for the regulation of LPS-induced B7.1 transcription. Furthermore, SP600125 and dexamethasone inhibited LPS-induced IRF-7 activity. Taken together, these results suggest that LPS-induced B7.1 transcription in human monocytic cells may be regulated by JNK-mediated activation of the IRF-7 transcription factor.
authors.affiliation: Department of Pathology and Laboratory Medicine University of Ottawa, Ottawa, Canada.
authors.forename: Wilfred
authors.initials: W
authors.lastname: Lim
authors.forename: Katrina
authors.initials: K
authors.lastname: Gee
authors.forename: Sasmita
authors.initials: S
authors.lastname: Mishra
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D018122:B7-1 Antigen / Q000235:genetics*; D001665:Binding Sites; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D000873:Anthracenes; D018122:B7-1 Antigen; D050839:Interferon Regulatory Factor-7; D008070:Lipopolysaccharides; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases