title: Bradykinin B1 receptor up-regulation by interleukin-1beta and B1 agonist occurs through independent and synergistic intracellular signaling mechanisms in human lung fibroblasts.
abstract: Bradykinin B1 receptors (B1R) are rapidly induced after tissue trauma and are thought to be involved in maintaining the inflammatory response. Little is known about the intracellular signaling pathways mediating B1R induction in response to stress and inflammation. Here, we show that up-regulation of B1R by B1R agonist and interleukin-1beta (IL-1beta) occur through distinct but synergistic pathways in IMR-90 human lung fibroblasts. Incubation of cells with the B1R agonist desArg10kallidin (desArg10KD; 100 nM) and IL-1beta (500 pg/ml) resulted in a 3- and 4-fold increase, respectively, in B1R by 6 h, whereas coincubation of these factors produced up to a 20-fold increase. Furthermore, coincubation increased the potency of IL-1beta by 2-fold. Both the individual and the synergistic responses were sensitive to genistein, a general tyrosine kinase inhibitor. On the other hand, only the desArg10KD response and the synergistic response were sensitive to the p38 mitogen-activated protein kinase inhibitor SB 203580. Furthermore, only the synergistic response was sensitive to the nuclear factor-kappaB inhibitor pyrrolidine dithiocarbamate. Despite B1R up-regulation in A549 human lung epithelial cells by desArg10KD or IL-1beta individually, these factors did not act synergistically in this cell line. In conclusion, our results reinforce the view that kinins act in concert with proinflammatory cytokines to enhance selectively the inflammatory response of certain lung cells to kinins through distinct but synergistic intracellular signaling mechanisms. Thus, kinins may exert a pivotal role in maintaining and modulating feed-forward inflammatory processes in the lung.
authors.affiliation: Developmental Biology Program, Department of Surgery, Childrens Hospital Los Angeles Research Institute, Los Angeles, California 90027, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Phagoo
authors.forename: K
authors.initials: K
authors.lastname: Reddi
authors.forename: K D
authors.initials: KD
authors.lastname: Anderson
authors.forename: L M
authors.initials: LM
authors.lastname: Leeb-Lundberg
authors.forename: D
authors.initials: D
authors.lastname: Warburton
mesh_terms: D002478:Cells, Cultured; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007609:Kallidin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016328:NF-kappa B; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases