IL-1beta-induced transcriptional up-regulation of bradykinin B1 and B2 receptors in murine airways.
Hyperresponsiveness to bronchoconstrictor stimuli is a major pathophysiologic feature of asthma, but the molecular mechanisms behind this are not fully understood. The release of TNF-alpha and IL-1beta during the inflammatory process is believed to play an important role in airway hyperresponsiveness. We have previously demonstrated, using a murine in vitro model of chronic airway inflammation, that TNF-alpha up-regulated bradykinin B(1) and B(2) receptors in the airway smooth muscle. By using the same model, the present study was designed to investigate the effects of IL-1beta and its interaction with TNF-alpha on the expression of bradykinin B(1) and B(2) receptors in mouse tracheal smooth muscle. IL-1beta up-regulated bradykinin B(1) and B(2) receptor expression and increased contractile response to bradykinin B(1) and B(2) receptor agonists (des-Arg(9)-bradykinin and bradykinin, respectively) in the tracheal smooth muscle. Transcriptional inhibitor actinomycin D, c-Jun N-terminal kinase (JNK) inhibitors SP600125 and TAT-TI-JIP(153-163), but not extracellular signal-regulated kinase 1 and 2 (ERK 1/2) inhibitor PD98059, significantly attenuated this up-regulation, indicating that a transcriptional mechanism and intracellular JNK signal transduction pathway were involved. In addition, IL-1beta did not affect bradykinin B(1) and B(2) receptor mRNA stability. Remicade, an anti-TNF-alpha antibody, markedly suppressed IL-1beta-induced up-regulation of bradykinin B(1) and B(2) receptors, suggesting that TNF-alpha was involved in the up-regulation, which is further supported by the fact that IL-1beta enhanced TNF-alpha mRNA expression in the tracheae. Intracellular JNK pathway and TNF-alpha might provide key links between inflammatory mediators like IL-1beta and airway hyperresponsiveness to bradykinin.
Zhang
Yaping
Y
Laboratory of Clinical and Experimental Allergy Research, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, SE 205 02 Malmö, Sweden. Yaping.Zhang@med.lu.se
Adner
Mikael
M
Cardell
Lars-Olaf
LO
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D000911:Antibodies, Monoclonal; D001249:Asthma / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D000069285:Infliximab; D053583:Interleukin-1beta / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014132:Trachea / Q000033:anatomy & histology / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D000069285:Infliximab; D048031:JNK Mitogen-Activated Protein Kinases; D001920:Bradykinin