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Mechanisms of interleukin 1β-induced human airway smooth muscle hyporesponsiveness to histamine: Involvement of p38 MAPK and NF-κB

American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X, Vol: 163, Issue: 4, Page: 1010-1017
2001
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Article Description

We have investigated the effect of IL-1β on histamine H-receptor (HR)-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-1β resulted in significant loss of histamine-induced IP formation, which was associated with a reduction of histamine-induced contraction of IL-1β-treated human bronchial rings. An inhibitor of NF-κB activation, pyrrolidine dithiocarbamate, and a p38 MAPK inhibitor, blocked the IL-1β-induced HR desensitization, whereas anisomycin, an SAPK/JNK and p38 MAPK activator, mimicked the effect of IL-1β. IL-1β has been demonstrated to induce cox-2 expression and PGE synthesis. In our study, indomethacin a cox antagonist, completely inhibited the effect of IL-1β on HR, whereas exogenously added PGE was able to desensitize HR. Furthermore, H-89, a selective PKA inhibitor, antagonized the effect of IL-1β. Here, we have demonstrated that IL-1β desensitizes HR, which involves the activation of p38 MAPK and NF-κB, leading to the expression of cox-2 and the synthesis of PGE. PGE increases intracellular cAMP resulting in PKA activation, which phosphorylates and functionally uncouples HR. Our results suggest that IL-1β protects airway smooth muscle against histamine-induced contractile responses and that bronchial hyperreactivity to histamine is not associated with proinflammatory cytokine-induced enhancement in HR signaling.

Bibliographic Details

JAN L. PYPE; HAIYAN XU; MARLEEN SCHUERMANS; LIEVEN J. DUPONT; WIM WUYTS; JUDITH C. W. MAK; PETER J. BARNES; MAURITS G. DEMEDTS; GEERT M. VERLEDEN

American Thoracic Society

Medicine

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