Effect of interferon- gamma on inflammatory cytokine-induced bradykinin B sub(1) receptor expression in human vascular cells

• Published in: European journal of pharmacology 2010-11, Vol.647 (1-3), p.117-125
• Main Authors: Koumbadinga, Geremy Abdull, Desormeaux, Anick, Adam, Albert, Marceau, Francois
• Format: Article
• Language: English
• Subjects: Antibodies
• ISSN: 0014-2999
• DOI: 10.1016/j.ejphar.2010.08.008

The expression of the bradykinin B sub(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)- alpha and interferon (IFN)- gamma by an upregulation of B sub(1) receptors and whether these pathways interact. B sub(1) receptor expression was quantified using a [ super(3)H]Lys-des-Arg super(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- alpha and IFN- gamma had a synergistic effect on B sub(1) receptor expression in both cell types, increasing primarily receptor abundance in both cell types (16 h) and mRNA concentration (4 h) in endothelial cells. The synergistic effect of the IFN- gamma -TNF- alpha combination was abated by drugs targeted at the signaling of either cytokine (for TNF- alpha : etanercept or the I Kappa B kinase 2 inhibitor TPCA-1; for IFN- gamma : neutralizing antibodies to IFN- gamma , a pan-Jak inhibitor but not the Jak2 inhibitor AG490). Thus, Jak2 signaling may not be recruited by the IFN- gamma receptors in vascular cells; however, Stat1 phosphorylation was correlated as expected to the effect of IFN- gamma on B sub(1) receptor expression. Random migration was inhibited by the B sub(1) receptor agonist Lys-des-Arg super(9)-bradykinin only in smooth muscle cells pretreated with the cytokine combination. The amplificatory effect of IFN- gamma on TNF- alpha -induced bradykinin B sub(1) receptor expression is relevant to vasculopathies associated with T helper 1 cytokines.