Retinoic Acids Are Potent Inhibitors of Spontaneous Human Eosinophil Apoptosis

Abstract

Retinoic acids (RAs), which are active metabolites of vitamin A, are known to enhance Th2-type immune responses in vitro, but the role of RAs in allergic inflammatory cells remains unclear. In this study, we demonstrated that purified peripheral blood eosinophils expressed nuclear receptors for RAs at the mRNA and protein levels. Eosinophils cultured with all-trans RA (ATRA) and 9-cis-RA showed dramatically induced cell survival and nuclear hypersegmentation, and the efficacy of RAs (10−6M) was similar to that of IL-5 (1 ng/ml), the most critical cytokine for eosinophil activation. Pharmacological manipulation with receptor-specific agonists and antagonists indicated that the antiapoptotic effect of RAs was mediated through ligand-dependent activation of both retinoid acid receptors and retinoid X receptors (mainly retinoid acid receptors). Furthermore, using a gene microarray and a cytokine Ab array, we discovered that RAs induced vascular endothelial growth factor, M-CSF, and MCP-1 secretion, although they were not involved in eosinophil survival. RA-induced eosinophil survival appears to be associated with down-regulation of caspase 3 and inhibition of its enzymatic activity. These findings indicate an important role of RAs in homeostasis of granulocytes and provide further insight into the cellular and molecular pathogenesis of allergic reactions.

Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine

“…Interestingly, IL-7 and IL-15 are well known to regulate T cell homeostasis in the small intestine and it is tempting to speculate that both cytokine synergistically might contribute to eosinophils survival in the intestine, either directly or indirectly by stimulation of classical hematopoietins. Moreover, retinoic acid has recently been reported to inhibit eosinophil apoptosis (23), adding another facet to the complex array of factors abundantly present in the intestine and connected to eosinophil survival.…”

Altered Eosinophil Proteome in a Patient with Hypereosinophilia from Acute Fascioliasis

“…Gelsolin is thought to play a role in degranulation (4) and adherence to target cells. The synaptic vesicle protein VAT-1 may play a role in antiapoptotic and prosurvival mechanisms, typical of several cytokines (11). The spot for ezrin was also increased, but this was not statistically significant.…”

Docosahexaenoic Acid Exerts Anti-Inflammatory Action on Human Eosinophils through Peroxisome Proliferator-Activated Receptor-Independent Mechanisms

“…Eosinophils were isolated by sedimentation with 6% dextran followed by centrifugation on 1.088 Percoll (Pharmacia, Uppsala, Sweden) density gradients. The cells were further purified by negative selection using anti-CD16 immunomagnetic beads and a MACS system (Miltenyi Biotec, Bergisch Gladbach, Germany) as previously described [13,14]. Eosinophil purity of >98% was routinely obtained.…”

“…Among their isoforms, PPARα and PPARγ are targets for various long-chain fatty acids, including n-3 PUFAs [12]. In the case of eosinophils, PPARγ might be involved; we previously reported that both PPARγ and its heterodimer partner, retinoid X receptor (RXR), were constitutively expressed in human peripheral blood eosinophils [13,14]. In addition, in vitro experiments have revealed that both selective PPARα agonists and PPARγ agonists inhibit eosinophil survival and eotaxin-induced chemotaxis [14,15,16].…”