Cutting Edge: Prostaglandin D2 Enhances Leukotriene C4 Synthesis by Eosinophils during Allergic Inflammation: Synergistic In Vivo Role of Endogenous Eotaxin

Abstract

In addition to the well-recognized ability of prostaglandin D2 (PGD2) to regulate eosinophil trafficking, we asked whether PGD2 was also able to activate eosinophils and control their leukotriene C4 (LTC4)-synthesizing machinery. PGD2 administration to presensitized mice enhanced in vivo LTC4 production and formation of eosinophil lipid bodies–potential LTC4-synthesizing organelles. Immunolocalization of newly formed LTC4 demonstrated that eosinophil lipid bodies were the sites of LTC4 synthesis during PGD2-induced eosinophilic inflammation. Pretreatment with HQL-79, an inhibitor of PGD synthase, abolished LTC4 synthesis and eosinophil lipid body formation triggered by allergic challenge. Although PGD2 was able to directly activate eosinophils in vitro, in vivo PGD2-induced lipid body-driven LTC4 synthesis within eosinophils was dependent on the synergistic activity of endogenous eotaxin acting via CCR3. Our findings, that PGD2 activated eosinophils and enhanced LTC4 synthesis in vivo in addition to the established PGD2 roles in eosinophil recruitment, heighten the interest in PGD2 as a target for antiallergic therapies.

Ultrastructural evidence for human mast cell-eosinophil interactions in vitro

“…Furthermore, the higher electron density of the lipid bodies in co-cultured MC can also be interpreted as MC activation, which stems from the new synthesis and/or accumulation of lipids and cytokines in the presence of Eos. Noteworthy, our results, which have been obtained with a relatively short incubation time (60 min), are in agreement with the data reported by Bandeira- Melo et al (2001) and by Mesquita-Santos et al (2006) who have demonstrated that these bodies can form in activated Eos and basophils after a 60-min incubation and can contribute to prostanoid synthesis and the amplification of the cell stimulation.…”

Polymorphisms of the PTGDR and LTC4S influence responsiveness to leukotriene receptor antagonists in Korean children with asthma

“…35 PTGDR expression was increased by the region including À441C allele 14 and increased expression of the PTGDR augmented the ability of PGD2 to recruit eosinophils and stimulate them to synthesize LTC4. 18 According to our data, the combined effects of the LTC4S À444C and PTGDR À441C alleles may have an additive effect on increasing TEC. Ultimately, higher levels of LTC4 disrupt LTRA responsiveness in children with asthma ( Figure 2).…”

“…The PGD2 recruits eosinophils 8 and induces the synthesis of LTC4 by stimulating the eosinophils. 18 Also the LTC4S À444A/C polymorphism was associated with leukotriene production and asthma in several independent studies. 25,26 Although the LTC4S À444A/C polymorphism was always not associated with asthma susceptibility or severity, 26,27 this polymorphism is universally most common SNP.…”

“…[15][16][17] However, the results of a recent study showed that PGD2 activated eosinophils and enhanced LTC4 synthesis in vivo. 18 Accumulating evidence suggests that the cysteinyl leukotrienes (cysLTs) are the primary mediators of exercise-induced bronchoconstriction (EIB), as demonstrated by the detection of cysLTs in the airways, 19 increased levels of urinary leukotriene E4 20 and increased levels of cysLTs in exhaled breath condensates, 21 and in induced sputum 22 from children with EIB. Therefore, we presume that the function of PGD2 may affect the response of the leukotriene receptor antagonist (LTRA), which inhibits the effect of leukotriene, although the PTGDR is not directly included in the LTRA pathway.…”

Cissampelos sympodialis (Menispermaceae): A Novel Phytotherapic Weapon Against Allergic Diseases?

“…Several inflammatory mediators are able to induce the leukocyte LB formation as platelet activator factor (PAF) (De Assis et al, 2003). In eosinophils other stimuli such as prostaglandin D2 (PGD 2 ) (Mesquita-Santos et al, 2006), IL-5 (Bozza et al, 1998), RANTES and eotaxin also induced the LB formation (Vieira-deAbreu et al, 2005). In addition, in the allergic inflammation, the new LBs are observed and this process is mediated mainly by a cross-talk between eotaxin/RANTES via chemokine receptors (CCR3) with MAPK, PI3K and tyrosine kinases activation and PGD2 via an unknown receptor.…”