MAP kinases mediate interleukin-13 effects on calcium signaling in human airway smooth muscle cells

Abstract

Interleukin-13 (IL-13) has been strongly implicated in the pathogenesis of allergic asthma through animal models that have shown that IL-13 is both necessary and sufficient to cause airway hyperresponsiveness (AHR). Airway smooth muscle (ASM) is a primary effector of AHR, and IL-13 increases the responsiveness of ASM, by increasing Ca(2+) release intracellularly, to bronchoconstrictors such as histamine. The mechanisms and signaling pathways mediating this effect are incompletely understood. We have investigated the pathways through which IL-13 regulates the Ca(2+) response to histamine in primary human ASM cell cultures. Functional IL-13 receptors were demonstrated by IL-13-mediated phosphorylation of signal transducer and activator of transcription 6 (STAT6) and mitogen-activated protein kinases (MAPKs). IL-13 increased Ca(2+) responses to histamine. The augmentation of Ca(2+) signaling was not affected by inhibition of STAT6 or p38 MAPK signaling but was prevented by concurrent inhibition of c-jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK) MAPKs. This inhibition did not affect the IL-13-induced increase in histamine receptors. We conclude that IL-13 induces potentiation of Ca(2+) responses to contractile agonists by affecting mechanisms downstream of receptors. JNK and ERK MAPKs modulate these mechanisms.

Dissociation of FK506-Binding Protein 12.6 kD from Ryanodine Receptor in Bronchial Smooth Muscle Cells in Airway Hyperresponsiveness in Asthma

“…These results indicate that cADPR does not contribute to airway inflammation-induced dissociation of FKBP12.6 from the RyR2. Ca 21 mobilization from SR in BSMCs in response to contractile agonists such as bradykinin or acetylcholine is an important component of smooth muscle contraction (12,28,30). When dissociated from FKBP12.6, the RyR2 calcium channel on the SR membrane has more opening probability and becomes sensitized to intracellular activator signals.…”

Enhanced airway smooth muscle cell thromboxane receptor signaling via activation of JNK MAPK and extracellular calcium influx

“…Consequently, it has been hypothesized that the intracellular calcium concentration is abnormally elevated in asthmatic airway smooth muscle cells (Amrani and Panettieri, 1998;Amrani et al, 2004;Moynihan et al, 2008). The U46619-induced tonic contractions in rat bronchi is dependent on the extracellular calcium concentration, while it was not affected by intracellular calcium pools (Parvez et al, 2006).…”

Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype

“…IL-13 has been shown to augment contractile responses to acetylcholine (ACh) and to impair relaxation to isoproterenol in rabbit tracheal smooth muscle (9) as well as isoproterenol-induced decrease in cell stiffness in cultured hASMC (18). Enhancement by IL-13 of Ca 2ϩ responses of cultured hASMC evoked by bradykinin, histamine, and ACh has been reported (30) and attributed to the increased expression of CD38 protein (3) and activation of MAP kinases (24). IL-13 stimulates the secretion of eotaxin (14,26) and IL-5 from ASMC (7).…”