Augmentation of allergic inflammation in prostanoid IP receptor deficient mice

Abstract

1 To evaluate the role of prostaglandin I 2 (PGI 2 ) in allergic in¯ammation, allergic responses in the airway, skin and T cells were studied in mice lacking the receptor for PGI 2 (the prostanoid IP receptor) through gene disruption. 2 Three inhalations of antigen caused an increase in plasma extravasation, leukocyte accumulation and cytokine (interleukin (IL)-4 and IL-5) production in the airway of sensitized mice. These airway in¯ammatory responses were signi®cantly greater in IP receptor de®cient mice than in wild-type mice.3 The vascular leakage caused by passive cutaneous anaphylaxis, substance P and 5-hydroxytryptamine was markedly increased in the skin of IP receptor de®cient mice, compared with comparably treated wild-type mice. 4 The inhalation of antigen in sensitized mice resulted in increased serum antigen speci®c IgE, total IgE and IgG levels. The magnitude of the elevations of each immunoglobulin level in IP receptor de®cient mice is notably higher than that in wild-type mice. To elucidate the mechanism of an enhancement of immunoglobulin production, the activity of T cells in sensitized and non-sensitized mice was studied by means of the production of cytokines. The antigen-induced IL-4 production by spleen cells from sensitized IP receptor de®cient mice was almost three times greater than that in wild-type mice. On the contrary, the anti-CD3 antibody-induced interferon-g production by CD4+ T cells from non-sensitized IP receptor de®cient mice was signi®cantly lower than that in wild-type mice. 5 The present data indicate that IP receptor de®ciency reinforced an allergic airway and skin in¯ammation by augmentation of vascular permeability increase and the T helper 2 cell function. These ®ndings suggest a regulatory role of PGI 2 in allergic in¯ammation.

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

“…PGD 2 and its receptors, DP and CRTH2, are known to be involved in chronic allergic skin inflammation (Angeli et al, 2004;Satoh et al, 2006). The marked increases in PGFS and PGIS that we noted in response to UVB also suggest that eicosanoids produced by these enzymes may be important mediators of cutaneous inflammation (Muller et al, 2000;Takahashi et al, 2002). Increases in expression of receptors for PGD 2α and prostacyclin provide further evidence that UVB stimulates both the capacity of keratinocytes to produce these prostaglandins and cellular responsiveness to these mediators.…”

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

“…An immunosuppressive effect of PGI 2 on Th2-mediated inflammation has been also demonstrated with an OVA-induced allergy model (2,3). IP-deficient mice (IP Ϫ/Ϫ ) exhibited increased allergic responses to OVA challenges compared with wild-type mice (IP ϩ/ϩ ) as indicated by increased leukocyte accumulation and IL-4 and IL-5 production in the airway of the sensitized animals (2,3). However, the cellular and molecular mechanisms of PGI 2 -mediated anti-inflammatory effects remain to be determined.…”

“…In contrast, overexpression of PGI 2 synthase in mouse lung epithelium protected mice from RSV-induced weight loss (1). An immunosuppressive effect of PGI 2 on Th2-mediated inflammation has been also demonstrated with an OVA-induced allergy model (2,3). IP-deficient mice (IP Ϫ/Ϫ ) exhibited increased allergic responses to OVA challenges compared with wild-type mice (IP ϩ/ϩ ) as indicated by increased leukocyte accumulation and IL-4 and IL-5 production in the airway of the sensitized animals (2,3).…”

“…P rostaglandin I 2 , also known as prostacyclin, is a metabolite of arachidonic acid that has been recently shown to have anti-inflammatory functions (1)(2)(3). In a murine respiratory syncytial virus (RSV) 3 infection model, we reported that deficiency of the PGI 2 receptor (IP) resulted in increased RSV-induced and inflammation-associated weight loss.…”

“…In a murine respiratory syncytial virus (RSV) 3 infection model, we reported that deficiency of the PGI 2 receptor (IP) resulted in increased RSV-induced and inflammation-associated weight loss. In contrast, overexpression of PGI 2 synthase in mouse lung epithelium protected mice from RSV-induced weight loss (1).…”