Effect of interferon-γ on inflammatory cytokine-induced bradykinin B1 receptor expression in human vascular cells.
The expression of the bradykinin B(1) receptor is strongly regulated in vascular tissue following injury, with little or no expression in healthy tissues. The present work aimed to verify whether primary human vascular cells (umbilical vein endothelial cells, umbilical artery smooth muscle cells) respond to tumor necrosis factor (TNF)-α and interferon (IFN)-γ by an upregulation of B(1) receptors and whether these pathways interact. B(1) receptor expression was quantified using a [(3)H]Lys-des-Arg(9)-bradykinin binding assay (cell surface protein) and RT-PCR (mRNA). A pharmacological approach exploiting several inhibitory drugs related to cytokine signaling was applied. The combined treatment with TNF-α and IFN-γ had a synergistic effect on B(1) receptor expression in both cell types, increasing primarily receptor abundance in both cell types (16 h) and mRNA concentration (4h) in endothelial cells. The synergistic effect of the IFN-γ-TNF-α combination was abated by drugs targeted at the signaling of either cytokine (for TNF-α: etanercept or the IκB kinase 2 inhibitor TPCA-1; for IFN-γ: neutralizing antibodies to IFN-γ, a pan-Jak inhibitor but not the Jak2 inhibitor AG490). Thus, Jak2 signaling may not be recruited by the IFN-γ receptors in vascular cells; however, Stat1 phosphorylation was correlated as expected to the effect of IFN-γ on B(1) receptor expression. Random migration was inhibited by the B(1) receptor agonist Lys-des-Arg(9)-bradykinin only in smooth muscle cells pretreated with the cytokine combination. The amplificatory effect of IFN-γ on TNF-α-induced bradykinin B(1) receptor expression is relevant to vasculopathies associated with T helper 1 cytokines.
Koumbadinga
Gérémy Abdull
GA
Centre de recherche en rhumatologie et immunologie, Centre Hospitalier Universitaire de Québec, Québec, Canada.
Désormeaux
Anick
A
Adam
Albert
A
Marceau
François
F
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D043783:Receptor, Bradykinin B1 / Q000032:analysis / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000032:analysis / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014470:Umbilical Cord / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000096743:Interferon gamma Receptor
D000970:Antineoplastic Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D016328:NF-kappa B; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D017471:Receptors, Interferon; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C494086:STAT3 protein, human