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

Abstract

We have investigated the effect of IL-1β 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-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 H 1R 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 2 synthesis. In our study, indomethacin a cox antagonist, completely inhibited the effect of IL-1β on H 1R, whereas exogenously added PGE 2 was able to desensitize H 1R. Furthermore, H-89, a selective PKA inhibitor, antagonized the effect of IL-1β. Here, we have demonstrated that IL-1β desensitizes H 1R, which involves the activation of p38 MAPK and NF-κB, 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 1R. 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 H 1R signaling.