Abstract

We investigated the hypothesis that inflammatory mediators such as interleukin-1β (IL-1β) might be responsible for the hyperreactivity of asthmatic patients to bradykinin. In cultured human bronchial smooth muscle cells, IL-1β elicited a rapid and transient increase in the density of bradykinin B₂ receptors without affecting their affinity for ligands. The increase in B₂ receptors was correlated to an enhancement of inositol phosphate formation elicited by bradykinin, indicating its relevance to the contractile response of smooth muscle cells to bradykinin. The increase in receptor density was related to an increase in B₂ receptor mRNA level corresponding to a 5-fold enhancement of the transcriptional rate and to a lengthened half-life of mRNA. These effects of IL-1β were largely inhibited by indomethacin, suggesting the involvement of a prostanoid pathway in IL-1β transduction process. An increase in prostaglandin E₂ levels preceded the mRNA increase, confirming this involvement. Moreover, IL-1β and prostaglandin E₂ led to cAMP formation. We propose this predominant transduction pathway of IL-1β to stimulate the transcription of the bradykinin B₂ gene in human bronchial smooth muscle cells as a major mechanism involved in the hyperresponsiveness of asthmatic patients to bradykinin.