Receptors and Signaling Mechanisms Required for Prostaglandin E2-Mediated Regulation of Mast Cell Degranulation and IL-6 Production

Abstract

Mast cells are implicated in the pathogenesis of a broad spectrum of immunological disorders. These cells release inflammatory mediators in response to a number of stimuli, including IgE-Ag complexes. The degranulation of mast cells is modified by PGs. To begin to delineate the pathway(s) used by PGs to regulate mast cell function, we examined bone marrow-derived mast cells (BMMC) cultured from mice deficient in the EP1, EP2, EP3, and EP4 receptors for PGE2. Although BMMCs express all four of these PGE2 receptors, potentiation of Ag-stimulated degranulation and IL-6 cytokine production by PGE2 is dependent on the EP3 receptor. Consistent with the coupling of this receptor to Gαi, PGE2 activation of the EP3 receptor leads to both inhibition of adenylate cyclase and increased intracellular Ca2+. The magnitude of increase in intracellular Ca2+ induced by EP3 activation is similar to that observed after activation of cells with IgE and Ag. Although PGE alone is not sufficient to initiate BMMC degranulation, stimulation of cells with PGE along with PMA induces degranulation. These actions are mediated by the EP3 receptor through signals involving Ca2+ mobilization and/or decreased cAMP levels. Accordingly, these studies identify PGE2/EP3 as a proinflammatory signaling pathway that promotes mast cell activation.

Synergistic activation of phospholipases Cγ and Cβ: A novel mechanism for PI3K-independent enhancement of FcεRI-induced mast cell mediator release

“…1B) of this molecule for further study. As described [17,18], PGE 2 alone failed to stimulate degranulation ( Fig 1B) but it significantly potentiated antigen-induced degranulation in a pertussis toxin (PTX)-sensitive manner (Fig. 1C).…”

“…However, as studies in human mast cells may be complicated by the additional inhibitory responses with GPCRs such as adenosine and PGE 2 [10], we elected to utilize mouse BMMCs for our studies. We screened several GPCR agonists, including S1P, adenosine, MIP1-α, Rantes, and PGE 2 , known to modify mast cell function [10][11][12]14,16,18], for their relative abilities to enhance antigen (DNP-human serum albumin (DNP-HSA))-mediated BMMC activation (Fig. 1A).…”

“…However, the antigen-mediated response may be markedly influenced by co-activation through other cell surface receptors and it has been suggested that these interactions may modulate mast celldriven reactions in situ [2,3]. Such receptors, which have been reported to induce mediator release by themselves, enhance antigen-mediated mast cell activation, or inhibit antigen-mediated mast cell activation, include the stem cell factor (SCF) receptor, Kit [4,5]; toll-like receptors (TLRs) such as TLR2 [6,7], TLR3 [8], and TLR4 [7,9]; and G protein-coupled receptors (GPCRs) [10] such as receptors for adenosine (A3 receptor) [11][12][13], macrophage inflammatory protein-1α (CCR1) [14], the complement component C3a (C3aR) [15], sphingosine-1-phosphate (SIP) (S1P 2 R) [16] and prostaglandin (PG)E 2 (EP1 and 3) [17][18][19]. It is unclear, however, how the signaling cascades initiated by these various classes of receptors are integrated with FcεRI-mediated signals to modify antigen-mediated mast cell activation.…”

Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases

“…IL-4 and IL-5 are the prototypic Th2 cytokines, and IL-12 is the critical inducer of a polarized Th1 response and plays a role in inhibiting Th2 response (101). In addition, PGE 2 also influences Th2-mediated humoral immune response by EP2/4 receptor-driven immunoglobulin class switching to IgE and EP3 receptor-dependent potentiation of mast cell degranulation (14,76). In spite of these in vitro data, it has been suggested that PGE 2 has a bronchoprotective effect in patients with bronchial asthma.…”

IFNγ-Dependent Interactions between ICAM-1 and LFA-1 Counteract Prostaglandin E2–Mediated Inhibition of Antitumor CTL Responses

“…7C and D). Together, these data clearly show that overexpression of ICAM-1 can counteract (33,34), it also inhibits cytokine release by macrophages (35). We have shown that the concentration of PGE 2 is a major factor in determining its overall affect upon CD8 þ T-cell responses.…”