Autoregulation of bradykinin receptors: agonists in the presence of interleukin-1beta shift the repertoire of receptor subtypes from B2 to B1 in human lung fibroblasts.
Elevated formation of bradykinin (BK) and Lys-BK or kallidin (KD) and their carboxypeptidase metabolites desArg(9)BK and desArg(10)KD is evident at sites of inflammation. Moreover, B2 receptors (B2R), which mediate the action of BK and KD, participates in the acute stage of the inflammatory and pain response, whereas B1 receptors (B1R), through which desArg(9)BK and desArg(10)KD act, partake in the chronic stage. We hypothesized that kinins autoregulate B2R and B1R expression in favor of B1R. Incubation of IMR-90 cells with BK (100 nM) led to a loss (89%) of B2R with a half-life (T(1/2)) of 7.0 min. Concomitantly, BK increased B1R (2- to 3-fold) with a T(1/2) of 120 min. DesArg(10)KD (100 nM) had no effect on B2R but increased B1R (3- to 4-fold) with the same rate as BK. Interleukin-1beta (IL-1beta; 500 pg/ml) also increased B1R (4- to 6-fold). Although both desArg(10)KD and BK increased the level of IL-1beta mRNA, IL-1beta receptor antagonist inhibited the increase in B1R only in response to BK. DesArg(10)KD and BK synergistically increased B1R (9-fold), which was further increased by inclusion of IL-1beta (36-fold). Therefore, kinin metabolism and kinin-stimulated production of cytokines may play a pivotal role in shifting the repertoire of kinin receptor subtypes in favor of B1R during inflammation.
Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, USA.
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Phagoo
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Poole
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Leeb-Lundberg
D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006868:Hydrolysis; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D010716:Phosphatidylinositols; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin