IL-1 –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 TNFand IL1 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 TNFup-regulated bradykinin B1 and B2 receptors in the airway smooth muscle. By using the same model, the present study was designed to investigate the effects of IL-1 and its interaction with TNFon the expression of bradykinin B1 and B2 receptors in mouse tracheal smooth muscle. IL-1 up-regulated bradykinin B1 and B2 receptor expression and increased contractile response to bradykinin B1 and B2 receptor agonists (des-Arg9-bradykinin and bradykinin, respectively) in the tracheal smooth muscle. Transcriptional inhibitor actinomycin D, c-Jun N-terminal kinase (JNK) inhibitors SP600125 and TAT-TI-JIP153–163, 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-1 did not affect bradykinin B1 and B2 receptor mRNA stability. Remicade, an anti–TNFantibody, markedly suppressed IL-1 –induced up-regulation of bradykinin B1 and B2 receptors, suggesting that TNFwas involved in the up-regulation, which is further supported by the fact that IL-1 enhanced TNFmRNA expression in the tracheae. Intracellular JNK pathway and TNFmight provide key links between inflammatory mediators like IL-1 and airway hyperresponsiveness to bradykinin.