This Article Full Text Full Text (PDF) All Versions of this Article: 2005-0369OCv1 36/6/697    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Cardell, L.-O. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Cardell, L.-O.

IL-1–Induced Transcriptional Up-Regulation of Bradykinin B₁ and B₂ Receptors in Murine Airways

Laboratory of Clinical and Experimental Allergy Research, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden

Correspondence and requests for reprints should be addressed to Yaping Zhang, Ph.D., Laboratory of Clinical and Experimental Allergy Research, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, SE 205 02 Malmö, Sweden. E-mail: Yaping.Zhang{at}med.lu.se

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- and IL-1 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- up-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 TNF- on 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-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-1 did not affect bradykinin B₁ and B₂ receptor mRNA stability. Remicade, an anti–TNF- antibody, markedly suppressed IL-1–induced up-regulation of bradykinin B₁ and B₂ receptors, suggesting that TNF- was involved in the up-regulation, which is further supported by the fact that IL-1 enhanced TNF- mRNA expression in the tracheae. Intracellular JNK pathway and TNF- might provide key links between inflammatory mediators like IL-1 and airway hyperresponsiveness to bradykinin.

Key Words: IL-1 • Remicade • bradykinin • receptor • JNK

CLINICAL RELEVANCE This article demonstrates how IL-1 that appears in bronchoalveolar lavage from individuals with asthma, induces airway hyperresponsiveness via up-regulation of bradykinin B1 and B2 receptors. This process involves TNF- and JNK, which might be of importance for the development of asthma.