Mechanisms of Interleukin 1 β -Induced Human Airway Smooth Muscle Hyporesponsiveness to Histamine

We have investigated the effect of IL-1 β 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 β resulted in significant loss of histamine-induced IP formation, which was associated with a reduction of histamine- induced contraction of IL-1 β -treated human bronchial rings. An inhibitor of NF- κ B activation, pyrrolidine dithiocarbamate, and a p38 MAPK inhibitor, blocked the IL-1 β -induced H1R desensitization, whereas anisomycin, an SAPK/JNK and p38 MAPK activator, mimicked the effect of IL-1 β . IL-1 β 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 β on H1R, whereas exogenously added PGE2 was able to desensitize H1R. Furthermore, H-89, a selective PKA inhibitor, antagonized the effect of IL-1 β . Here, we have demonstrated that IL-1 β desensitizes H1R, which involves the activation of p38 MAPK and NF- κ 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 β 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.