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Title: Mechanisms of interleukin 1beta-induced human airway smooth muscle hyporesponsiveness to histamine. Involvement of p38 MAPK NF-kappaB
Authors: Pype, J L ×
Xu, H
Schuermans, Mieke
Dupont, Lieven
Wuyts, Wim
Mak, J C
Barnes, P J
Demedts, M
Verleden, Geert #
Issue Date: Apr-2001
Series Title: American Journal of Respiratory and Critical Care Medicine vol:163 issue:4 pages:1010-7
Abstract: We have investigated the effect of IL-1beta on histamine H(1)-receptor (H(1)R)-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-1beta resulted in significant loss of histamine-induced IP formation, which was associated with a reduction of histamine- induced contraction of IL-1beta-treated human bronchial rings. An inhibitor of NF-kappaB activation, pyrrolidine dithiocarbamate, and a p38 MAPK inhibitor, blocked the IL-1beta-induced H(1)R desensitization, whereas anisomycin, an SAPK/JNK and p38 MAPK activator, mimicked the effect of IL-1beta. IL-1beta 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-1beta on H(1)R, whereas exogenously added PGE(2) was able to desensitize H(1)R. Furthermore, H-89, a selective PKA inhibitor, antagonized the effect of IL-1beta. Here, we have demonstrated that IL-1beta desensitizes H(1)R, which involves the activation of p38 MAPK and NF-kappaB, leading to the expression of cox-2 and the synthesis of PGE(2). PGE(2) increases intracellular cAMP resulting in PKA activation, which phosphorylates and functionally uncouples H(1)R. Our results suggest that IL-1beta protects airway smooth muscle against histamine-induced contractile responses and that bronchial hyperreactivity to histamine is not associated with proinflammatory cytokine-induced enhancement in H(1)R signaling.
ISSN: 1073-449X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Pneumology
× corresponding author
# (joint) last author

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