PIP3 Regulation as Promising Targeted Therapy of Mast-Cell-Mediated Diseases

Bruce      J. Shenker; Hydar      Ali; Kathleen      Boesze-Battaglia

Abstract

It is well established that mast cells play a key regulatory role in allergy and inflammation involving engagement of antigen with IgE bound to high-affinity IgE receptors (Fc??RI). The most aggressive efforts in regulating mast cell function have focused on selectively inhibiting cell activation and subsequent mediator synthesis and release, or alternatively, blocking the action of proinflammatory mediators in order to prevent or reduce disease severity. More recently, the goal for rationally designed pharmacotherapy has shifted focus to targeting and disrupting signaling pathways leading to inhibition of specific cell function(s). In this context, the PI-3K/PIP3/Akt pathway represents a potent target for pharmacologic intervention in mast cell-mediated inflammatory disorders. A pivotal component of this cascade is the activation of phosphatidylinositol-3-kinase (PI-3K) leading to a rise in intracellular levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 has broad effects on mast cell signaling and function as well as on proliferation and survival. We propose that PIP3 represents a potent target for developing therapeutic approaches to down regulate mast cell function and, in turn, reduce the severity of mast cell dependent disease. In this article we review approaches that have been taken to regulate the PI-3K pathway in mast cells. Moreover, we review a novel approach to target the signaling lipid, PIP3, and deplete intracellular levels of this phosphoinositol using a chimeric toxin composed of the Fc??RI binding region of IgE and the active subunit of the cytolethal distending toxin, CdtB, which we have recently demonstrated to function as a PIP3 phosphatase.

Keywords: Glycerophosphates, phosphatidic acids, glycerosphingolipids, phosphatidylinositols, cytolethal distending toxin, pharmacology, bacterial toxins, Gram-negative pathogens, cytokines, chemokines