Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes

Abstract

We have reported previously that PGE(2) inhibits dendritic cells (DC) functions. Because E prostanoid receptor (EPR) subtypes involved in this action are unknown, expression and functions of these receptors were examined in DC. Western blot and flow cytometry analyses showed that all EPRs were coexpressed in DC. In a dose-dependent manner, lipopolysaccharide (LPS) enhanced EP(2)R/EP(4)R but not EP(1)R/EP(3)R expressions. NS-398, a cyclooxygenase (COX)-2-selective inhibitor, suppressed LPS-enhanced EP(2)R/EP(4)R expression, suggesting that COX-2-issued prostaglandin E(2) (PGE(2)) modulates DC function through stimulation of specific EPR subtypes. Using selective agonists, we found that butaprost, an EP(2)R agonist, and PGE(1) alcohol, an EP(2)R and EP(2)R/EP(4)R agonist, inhibited major histocompatibility complex class II expression and enhanced interleukin-10 production from DC. However, no effect was observed with sulprostone and 17-phenyl-omega-trinor-PGE(2), selective agonists for EP(1)R and EP(1)R/EP(3)R, respectively. Treatment of DC with dibutyryl cyclic adenosine monophosphate (cAMP), an analog of cAMP, mimics PGE(2)-induced, inhibitory effects. Taken together, our data demonstrate that EP(2)R/EP(4)R are efficient for mediating PGE(2)-induced modulation of DC functions.

Prostaglandin I2 Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells

“…It has been shown that induction of cAMP has been associated with the modulatory effects of cAMPelevating agents including db-cAMP, forskolin, and the phosphodiesterase inhibitor IBMX. These reagents inhibited IL-12, TNF-␣, and MIP-1␣, while increasing IL-10 production by BMDCs (22,38,39). A similar effect of cAMP-elevating agents has been reported on BM-derived macrophages (40).…”

“…PGE 2 is another PG that has anti-inflammatory properties (22,38,49). Similar to the effect of PGI 2 analogs, PGE 2 has been shown to inhibit IL-12, TNF-␣, and IL-6 production by BMDCs, suppress MHC class II expression, and enhance IL-10 production (22,29,38,39). Studies showed that DCs may be activated to produce high levels of proinflammatory cytokines and remain at sites of inflammation or develop into CCR7-expressing cells that allow them to migrate to the draining lymph nodes and induce Ag-specific immune responses (50,51).…”

Polyunsaturated Fatty Acids Block Dendritic Cell Activation and Function Independently of NF-κB Activation

“…In general, EA interferes with synthesis and effects of AA-derived eicosanoids that are probably biologically more active (59). PGE 2 that is derived from AA is generally regarded as pro-inflammatory, but down-regulates IL-12 production of DC (52,58). Hence, a PGE 2 -dependent autocrine negative regulation of DCs may exist (60).…”

“…PUFAs, particularly AA, are substrates of COX and LOX for synthesis of eicosanoids (prostaglandins, leukotrienes) that influence DC function (19,57,58). In general, EA interferes with synthesis and effects of AA-derived eicosanoids that are probably biologically more active (59).…”

Eicosanoids, Prostaglandins, and the Progression of Tuberculosis

“…PGE2 expressed by antigen-presenting cells is critical in polarizing immune responses [8]. For example, it has recently been reported that PGE2 inhibits activation-induced cell death (AICD) in Th2 cells, thus polarizing adaptive immunity towards a Th1-type response [9].…”