Interleukin-1beta induces bradykinin B2 receptor gene expression through a prostanoid cyclic AMP-dependent pathway in human bronchial smooth muscle cells.
We investigated the hypothesis that inflammatory mediators such as interleukin-1beta (IL-1beta) might be responsible for the hyperreactivity of asthmatic patients to bradykinin. In cultured human bronchial smooth muscle cells, IL-1beta 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-1beta were largely inhibited by indomethacin, suggesting the involvement of a prostanoid pathway in IL-1beta transduction process. An increase in prostaglandin E2 levels preceded the mRNA increase, confirming this involvement. Moreover, IL-1beta and prostaglandin E2 led to cAMP formation. We propose this predominant transduction pathway of IL-1beta 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.
Schmidlin
F
F
Laboratoire de Neuroimmunopharmacologie Pulmonaire, INSERM U425, Université Louis Pasteur Strasbourg I, Faculté de Pharmacie, 67401 Illkirch Cedex, France.
Scherrer
D
D
Daeffler
L
L
Bertrand
C
C
Landry
Y
Y
Gies
J P
JP
D001980:Bronchi / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics / Q000502:physiology*; D015232:Dinoprostone / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000378:metabolism*; D011453:Prostaglandins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000235:genetics*
D007375:Interleukin-1; D011453:Prostaglandins; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D000242:Cyclic AMP; D015232:Dinoprostone