Differential Regulation Of Cysteinyl Leukotriene Receptor Signaling By Protein Kinase C In Human Mast Cells

Differential Regulation Of Cysteinyl Leukotriene Receptor Signaling By Protein Kinase C In Human Mast Cells

Kondeti V; Duah E; Al-Azzam N; Thodeti C K; Boyce J A; Paruchuri S

Plos One

2013

2013-08

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, CysLT(1)R and CysLT(2)R. Although protein kinase C (PKC) isoforms are implicated in the regulation of CysLT(1)R 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 CysLT(1)R in MCs. In contrast, inhibition of PKCs suppressed c-fos expression as well MIP1 beta generation by cys-LTs. Interestingly, cys-LTs activated both PKC alpha and PKC epsilon isoforms in MC. However, knockdown of PKC alpha augmented cys-LT mediated calcium flux, while knockdown of PKC epsilon attenuated cys-LT induced c-fos expression and MIP1 beta generation. Taken together, these results demonstrate for the first time that cys-LT signaling downstream of CysLT(1)R in MCs is differentially regulated by two distinct PKCs which modulate inflammatory signals that have significant pathobiologic implications in allergic reactions and asthma pathology.

activation; antagonist; asthmatic subjects; desensitization; expression; hyperresponsiveness; intestinal epithelial-cells; proliferation; pulmonary inflammation; responses; Science & Technology - Other Topics

Journal Article or Conference Abstract Publication

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