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α- Galactosylceramide suppresses murine eosinophil production through interferon-γ-dependent induction of NO synthase and CD95.
- Source :
-
British Journal of Pharmacology . Jul2015, Vol. 172 Issue 13, p3313-3325. 13p. 1 Chart, 7 Graphs. - Publication Year :
- 2015
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Abstract
- Background and Purpose α- Galactosylceramide (α- GalCer), a pleiotropic immunomodulator with therapeutic potential in neoplastic, autoimmune and allergic diseases, activates invariant natural killer T-cells through CD1-restricted receptors for α- GalCer on antigen-presenting cells, inducing cytokine secretion. However the haemopoietic effects of α- GalCer remain little explored. Experimental Approach α- GalCer-induced modulation of eosinophil production in IL-5-stimulated bone marrow cultures was examined in wild-type ( BALB/c, C57BL/6) mice and their mutants lacking CD1, inducible NOS ( iNOS), CD95 and IFN-γ, along with the effects of lymphocytes; IFN-γ; caspase and iNOS inhibitors; non-steroidal anti-inflammatory drugs ( NSAIDs) and LTD4; and dexamethasone. Key Results α-GalCer (10−6-10−8M) suppressed IL-5-stimulated eosinopoiesis by inducing apoptosis. α-GalCer pretreatment in vivo (100 μg·kg−1, i.v.) suppressed colony formation by GM-CSF-stimulated bone marrow progenitors in semi-solid cultures. α- GalCer and dexamethasone synergistically promoted eosinophil maturation. Suppression of eosinophil production by α- GalCer was prevented by aminoguanidine and was undetectable in bone marrow lacking iNOS, CD95, CD28; or CD1d. Separation on Percoll gradients and depletion of CD3+ cells made bone marrow precursors unresponsive to α-GalCer. Responsiveness was restored with splenic lymphocytes. Experiments with (i) IFN-γ-deficient bone marrow, alone or co-cultured with spleen T-cells from wild-type, but not from CD1d-deficient, donors; (ii) IFN-γ neutralization; and (iii) recombinant IFN-γ, showed that these effects of α-GalCer were mediated by IFN-γ. Effects of α- GalCer on eosinophil production were blocked by LTD4 and NSAIDs. Conclusions and Implications α- GalCer activation of IFN-γ-secreting, CD1d-restricted lymphocytes induced iNOS- CD95-dependent apoptosis in developing eosinophils. This pathway is initiated by endogenous regulatory lymphocytes, antagonised by LTD4, NSAIDs and aminoguanidine, and modified by dexamethasone. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 172
- Issue :
- 13
- Database :
- Academic Search Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 103341064
- Full Text :
- https://doi.org/10.1111/bph.13126