prostaglandin-d2 and Dermatitis--Contact

Prostaglandins (PGs) are potent eicosanoid lipid mediators derived from phospholipase-released arachidonic acid, which are involved in numerous homeostatic biological functions and inflammation. They are generated by the sequential action of cyclooxygenase isozymes and cell-specific PG synthases. Along with their role in inflammatory responses, recent accumulating evidence strongly suggests that PGs, including PGD2, are part of a complex regulatory network that modulates the immune system. PGD2 is the major prostanoid secreted by activated mast cells and has long been implicated in allergic diseases. The aim of this review is to discuss our current understanding of the mode of action of PGD2 during Th2-mediated inflammation. We also discuss recent findings, which suggest that PGD2 exerts important effects on both immune and inflammatory responses by targeting the D prostanoid receptor 1 on dendritic cells, the most potent antigen-presenting cells.

Topics: Animals; Dendritic Cells; Dermatitis, Atopic; Dermatitis, Contact; Humans; Inflammation; Lipids; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Th2 Cells

Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell "stabilizer", is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD(2). Que and cromolyn also inhibit histamine, leukotrienes and PGD(2) from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption.

Topics: Anti-Allergic Agents; Antibodies, Anti-Idiotypic; Antigen-Antibody Complex; Calcium; Cells, Cultured; Cromolyn Sodium; Dermatitis, Contact; Histamine; Humans; Hypersensitivity; Immunoglobulin E; Interleukin-6; Interleukin-8; Leukotrienes; Mast Cells; NF-kappa B; Prostaglandin D2; Quercetin

Prostaglandin D2 (PGD2) exerts its effects through two distinct receptors: the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and the D prostanoid (DP) receptor. Our previous study demonstrated that CRTH2 mediates contact hypersensitivity (CHS) in mice. However, the function of DP receptor remains to be fully established. In this study, we examine the pathophysiological roles of PGD2 using DP-deficient (DP(-/-)) and CRTH2/DP-deficient (CRTH2(-/-)/DP(-/-)) mice to elucidate receptor-mediated PGD2 action in CHS. We observed profound exacerbation of CHS in DP(-/-) mice. CRTH2(-/-)/DP(-/-) mice showed similar exacerbation, but to a lesser extent. These symptoms were accompanied by increased production of interferon-γ and IL-17. The increase in IL-17 producing γδ T cells was marked and presumably contributed to the enhanced CHS. DP deficiency promoted the in vivo migration of dendritic cells to regional lymph nodes. A DP agonist added to DCs in vitro was able to inhibit production of IL-12 and IL-1β. Interestingly, production of IL-10 in dendritic cells was elevated via the DP pathway, but it was lowered by the CRTH2 pathway. Collectively, PGD2 signals through CRTH2 to mediate CHS inflammation, and conversely, DP signals to exert inhibitory effects on CHS. Thus, we report opposing functions for PGD2 that depend on receptor usage in allergic reactions.

Topics: Animals; Blotting, Western; Cell Movement; Chemokines; Cytokines; Dermatitis, Contact; Female; Flow Cytometry; Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; Inflammation; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-1beta; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes, Regulatory

Prostaglandin D2 (PGD2) is a prostanoid implicated in allergic inflammation. However, the roles of PGD2 in immune and allergic responses remain controversial. PGD2 exerts its effect through the CRTH2 and DP receptors. To elucidate functional differences of PGD2 and its receptors in chronic skin inflammation, chronic contact hypersensitivity (chronic CHS) and IgE-mediated chronic allergic skin inflammation (IgE-CAI) were induced in mice deficient in the CRTH2 and/or DP genes. DP (-/-) mice and CRTH2 (-/-)/DP (-/-) mice showed exacerbated chronic CHS, and conversely, CRTH2 (-/-) mice exhibited diminished skin responses. Skin responses correlated with local levels of IL-13, CCL11, and CCL22. These phenotypic changes in chronic CHS of mutant mice were similar to those in acute CHS despite the differences in the cytokine milieus; chronic CHS and acute CHS were mediated by Th2 and Th1/Th17 immunity, respectively. However, in IgE-CAI, DP (-/-) mice showed comparable skin responses to wild-type mice. Alleviation of IgE-CAI was observed in CRTH2 (-/-) mice, and as a consequence, CRTH2 (-/-)/DP (-/-) mice exhibited diminished IgE-CAI compared with wild-type mice. IgE-CAI in mutant mice correlated with local IL-4 and CCL22 production. Consistent with these results, a CRTH2-specific antagonist exerted inhibitory effects in both chronic CHS and IgE-CAI. The present study demonstrates that functional roles of PGD2 and its receptors appear to depend on the nature of the inflammation. Nevertheless, tools targeted against PGD2-CRTH2 signals could offer therapeutic potential for both types of chronic skin inflammation.

Topics: Animals; Dermatitis, Contact; Immunohistochemistry; Inflammation; Mice; Mice, Inbred BALB C; Mice, Knockout; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin