Abstract
Cysteinyl leukotrienes (cys-LTs) are a group of lipid mediators that are potent bronchoconstrictors, powerful inducers of vascular leakage and potentiators of airway hyperresponsiveness. Cys-LTs play an essential role in asthma and are synthesized as well as activated in mast cells (MCs). Cys-LTs relay their effects mainly through two known GPCRs, CysLT1R and CysLT2R. Although protein kinase C (PKC) isoforms are implicated in the regulation of CysLT1R function, neither the role of PKCs in cys-LT-dependent MC inflammatory signaling nor the involvement of specific isoforms in MC function are known. Here, we show that PKC inhibition augmented LTD4 and LTE4-induced calcium influx through CysLT1R in MCs. In contrast, inhibition of PKCs suppressed c-fos expression as well MIP1β generation by cys-LTs. Interestingly, cys-LTs activated both PKCα and PKCε isoforms in MC. However, knockdown of PKCα augmented cys-LT mediated calcium flux, while knockdown of PKCε attenuated cys-LT induced c-fos expression and MIP1β generation. Taken together, these results demonstrate for the first time that cys-LT signaling downstream of CysLT1R in MCs is differentially regulated by two distinct PKCs which modulate inflammatory signals that have significant pathobiologic implications in allergic reactions and asthma pathology.
Highlights
Cysteinyl leukotrienes, comprising LTC4, LTD4 and LTE4. are potent bronchoconstrictors and mediators of pulmonary inflammation [1,2]
We have demonstrated earlier that stimulation of human cord blood-derived mast cells (MCs) and/or LAD2 cells with LTD4 potently induces calcium flux [21,22] and cytokine generation [22,23], each of which requires CysLT1R based on pharmacologic antagonism by MK571. hMCs proliferate in response to LTD4, reflecting transactivation of c-kit by CysLT1R [24]
This signal was sensitive to inhibition by MK571, implying a requirement for CysLT1R or a CysLT1R-like G protein-coupled receptor (GPCR) in this signaling event
Summary
Cysteinyl leukotrienes (cys-LTs), comprising LTC4, LTD4 and LTE4. are potent bronchoconstrictors and mediators of pulmonary inflammation [1,2]. Bronchoalveolar lavage (BAL) fluids collected from allergic human subjects after endobronchial challenge with allergen contain high levels of cys-LTs [6], pointing the role of cys-LTs in allergic inflammation. This role is confirmed by the fact that inhibitors of the type 1 G protein-coupled receptor (GPCR) for cys-LTs (CysLT1R) [7,8] and inhibitors of cys-LT synthesis [9] are clinically efficacious for the treatment of asthma. Identification of signaling partners and mechanisms involved in the regulation of these receptors is crucial to gain insight into allergic inflammation
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