Mast cells play critical roles in hypersensitivity and in defense against certain parasites. We provide evidence that mouse mast cell survival and growth are promoted by monomeric IgE binding to its high-affinity receptor, Fc epsilon RI. Monomeric IgE does not promote DNA synthesis but suppresses the apoptosis induced by growth factor deprivation. This antiapoptotic effect occurs in parallel with IgE-induced increases in Fc epsilon RI surface expression but requires the continuous presence of IgE. This process does not involve the FasL/Fas death pathway or several Bcl-2 family proteins and induces a distinctly different signal than Fc epsilon RI cross-linking. The ability of IgE to enhance mast cell survival and Fc epsilon RI expression may contribute to amplified allergic reactions.

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IntroductionTumor-induced immune suppression is a fundamental problem in cancer biology and immunotherapy. COX metabolites act as tumor promoters when overproduced (1-3), and recent studies have demonstrated that the COX metabolite prostaglandin E 2 (PGE 2 ) exhibits potent immunosuppressive effects, orchestrating an imbalance between type 1 and type 2 cytokines (4-6). PGE 2 mediates its effects, in part, through G proteincoupled PGE receptors, designated EP1, EP2, EP3, and EP4. Differential expression of these EP receptors mediate the diverse, and often antagonistic, effects of PGE 2 and its analogues on a variety of cell types (7-9). The EP2 receptor regulates the activation and differentiation of mouse B lymphocytes (10), modulates T cell development (11-12), and regulates macrophage cytokine release (13) and postsurgery immune responses (14). The EP2 receptor also plays a key role in the differentiation of macrophage-like osteoclast cells as well as the functional response of osteoclasts to PGE 2 (15). Importantly, PGE 2 has been shown to be a key modulator of DC function, altering cytokine production as well as the I-A d class II cell surface marker (16)(17). Despite data describing the production of PGE 2 by tumors and the expression of the EP2 receptor in specific immune populations, the role of the EP2 receptor in modulation of the host immune response to tumors remains uncharacterized.Previous studies show that COX-2 and PGE 2 can play important roles in tumor angiogenesis (3,18,19). Recent publications show that in Apc ∆716 mice, a mouse model for human familial adenomatous polyposis, homozygous deletion of the gene encoding EP2 decreases the number and size of intestinal polyps through inhibition of tumor angiogenesis (19,20). In this study we determined the role of the EP2 receptor in host-tumor interactions. Unlike the results observed in the Apc ∆716 model, we observed no effect of the disruption of the EP2 receptor on tumor angiogenesis. We then examined the role of the EP2 receptor in T cell function, as well as DC differentiation, and functional responses to tumor challenge. Our data demonstrate an important role for the EP2

IntroductionTumor-induced immune suppression is a fundamental problem in cancer biology and immunotherapy. COX metabolites act as tumor promoters when overproduced (1-3), and recent studies have demonstrated that the COX metabolite prostaglandin E 2 (PGE 2 ) exhibits potent immunosuppressive effects, orchestrating an imbalance between type 1 and type 2 cytokines (4-6). PGE 2 mediates its effects, in part, through G proteincoupled PGE receptors, designated EP1, EP2, EP3, and EP4. Differential expression of these EP receptors mediate the diverse, and often antagonistic, effects of PGE 2 and its analogues on a variety of cell types (7-9). The EP2 receptor regulates the activation and differentiation of mouse B lymphocytes (10), modulates T cell development (11-12), and regulates macrophage cytokine release (13) and postsurgery immune responses (14). The EP2 receptor also plays a key role in the differentiation of macrophage-like osteoclast cells as well as the functional response of osteoclasts to PGE 2 (15). Importantly, PGE 2 has been shown to be a key modulator of DC function, altering cytokine production as well as the I-A d class II cell surface marker (16)(17). Despite data describing the production of PGE 2 by tumors and the expression of the EP2 receptor in specific immune populations, the role of the EP2 receptor in modulation of the host immune response to tumors remains uncharacterized.Previous studies show that COX-2 and PGE 2 can play important roles in tumor angiogenesis (3,18,19). Recent publications show that in Apc ∆716 mice, a mouse model for human familial adenomatous polyposis, homozygous deletion of the gene encoding EP2 decreases the number and size of intestinal polyps through inhibition of tumor angiogenesis (19,20). In this study we determined the role of the EP2 receptor in host-tumor interactions. Unlike the results observed in the Apc ∆716 model, we observed no effect of the disruption of the EP2 receptor on tumor angiogenesis. We then examined the role of the EP2 receptor in T cell function, as well as DC differentiation, and functional responses to tumor challenge. Our data demonstrate an important role for the EP2

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