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Mechanisms of Interleukin 1�-Induced Human Airway Smooth Muscle Hyporesponsiveness to Histamine Involvement of p38 MAPK and NF-�B

By Jan L. Pype, Haiyan Xu, Marleen Schuermans, Lieven J. Dupont, Wim Wuyts, Judith C. W. Mak, Peter J. Barnes, Maurits G. Demedts and Geert M. Verleden


We have investigated the effect of IL-1 � on histamine H 1-receptor (H 1R)-mediated inositol phosphate (IP) accumulation in human airway smooth muscle cells (HASMC) and on histamine-induced contraction of human bronchial rings. Stimulation of HASMC for 24 h with IL-1 � resulted in significant loss of histamine-induced IP formation, which was associated with a reduction of histamineinduced contraction of IL-1�-treated human bronchial rings. An inhibitor of NF-�B activation, pyrrolidine dithiocarbamate, and a p38 MAPK inhibitor, blocked the IL-1�-induced H 1R desensitization, whereas anisomycin, an SAPK/JNK and p38 MAPK activator, mimicked the effect of IL-1�. IL-1 � has been demonstrated to induce cox-2 expression and PGE 2 synthesis. In our study, indomethacin a cox antagonist, completely inhibited the effect of IL-1 � on H 1R, whereas exogenously added PGE 2 was able to desensitize H 1R. Furthermore, H-89, a selective PKA inhibitor, antagonized the effec

Year: 2013
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