Modulation of Mast Cell Proliferative and Inflammatory Responses by Leukotriene D₄ and Stem Cell Factor Signaling Interactions

Abstract

Mast cells (MCs) are important effector cells in asthma and pulmonary inflammation, and their proliferation and maturation is maintained by stem cell factor (SCF) via its receptor, c-Kit. Cysteinyl leukotrienes (cys-LTs) are potent inflammatory mediators that signal through CysLT1R and CysLT2R located on the MC surface, and they enhance MC inflammatory responses. However, it is not known if SCF and cys-LTs cross-talk and influence MC hyperplasia and activation in inflammation. Here, we report the concerted effort of the growth factor SCF and the inflammatory mediator LTD4 in MC activation. Stimulation of MCs by LTD4 in the presence of SCF enhances c-Kit-mediated proliferative responses. Similarly, SCF synergistically enhances LTD4-induced calcium, c-fos expression and phosphorylation, as well as MIP1β generation in MCs. These findings suggest that integration of SCF and LTD4 signals may contribute to MC hyperplasia and hyper-reactivity during airway hyper-response and inflammation.

Leukotriene D 4 and prostaglandin E 2 signals synergize and potentiate vascular inflammation in a mast cell–dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3

“…12 We also found that LTD 4 potentiates endothelial cell adhesion mediated by TNF-α, 20 suggesting that cys-LTs can modulate inflammation by acting in concert with other inflammatory mediators. Indeed, findings from the present study revealed that LTD 4 and PGE 2 produced at the inflammation site can synergistically activate MCs and further enhance inflammation.…”

“…We have previously demonstrated that stimulation of human cord blood–derived mast cells (hMCs), LAD2 cells, or both with LTD 4 potently induces calcium flux and cytokine generation 8 through CysLT 1 R. Additionally, MC proliferative and inflammatory responses are modulated by LTD 4 and stem cell factor (SCF) signaling interactions. 12 PGs have also been shown to elicit vasodilation and an increase in blood flow. Among PGs, PGE 2 is the most abundantly synthesized PG at the inflammation site and is regarded as an important regulator of inflammation.…”

Sphingosine-1-phosphate and other lipid mediators generated by mast cells as critical players in allergy and mast cell function

“…Thus, the mitogenic pathways induced by CysLT 1 receptors are in part convergent with those of KIT, but also distinct (Jiang et al, 2006), as supported by the synergistic effects of Cys-LT and SCF on the proliferation of mast cells (Al-Azzam et al, 2014). On the other hand, SCF can also induce Cys-LT production in mast cells and blockage of its production or antagonism of CysLT 1 receptor in vivo , substantially reduces the airway hyperresponsiveness induced after intra-tracheal instillation of SCF in mice (Oliveira et al, 2001).…”

Regulation of inflammation by lipid mediators in oral diseases

“…The Cys-LTs (i.e., LTC 4 , LTD 4 LTE 4 ) act on one of two cysteinyl leukotriene receptors (CYSLTR1 and CYSLTR2) (Kanaoka and Boyce, 2014). The exact downstream pathways of Cys-LTs are also unclear, but it is known that LTD 4 activates c-kit (Al Azzam et al, 2015), while LTE 4 activates PPARc (Paruchuri et al, 2008). Cys-LT activity can be regulated with protein kinase C (Kondeti et al, 2013).…”