Am. J. Respir. Crit. Care Med., Volume 163, Number 4, March 2001, 1010-1017

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

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

Katholieke Universiteit Leuven, Laboratory of Pneumology, Leuven, Belgium; and Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom

We have investigated the effect of IL-1 on histamine H₁-receptor (H₁R)-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 histamine- induced 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 H₁R 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 PGE₂ synthesis. In our study, indomethacin a cox antagonist, completely inhibited the effect of IL-1 on H₁R, whereas exogenously added PGE₂ was able to desensitize H₁R. Furthermore, H-89, a selective PKA inhibitor, antagonized the effect of IL-1. Here, we have demonstrated that IL-1 desensitizes H₁R, which involves the activation of p38 MAPK and NF-B, leading to the expression of cox-2 and the synthesis of PGE₂. PGE₂ increases intracellular cAMP resulting in PKA activation, which phosphorylates and functionally uncouples H₁R. Our results suggest that IL-1 protects airway smooth muscle against histamine-induced contractile responses and that bronchial hyperreactivity to histamine is not associated with proinflammatory cytokine-induced enhancement in H₁R signaling.

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