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α‐ G alactosylceramide suppresses murine eosinophil production through interferon‐γ‐dependent induction of NO synthase and CD 95
Author(s) -
GasparElsas Maria Ignez,
Queto Túlio,
MasiddeBrito Daniela,
Vieira Bruno Marques,
Luca Bianca,
Cunha Fernando Queiroz,
XavierElsas Pedro
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13126
Subject(s) - bone marrow , eosinophil , biology , immunology , cytokine , chemistry , asthma
Background and Purpose α‐ G alactosylceramide (α‐ GalCer ), a pleiotropic immunomodulator with therapeutic potential in neoplastic, autoimmune and allergic diseases, activates invariant natural killer T ‐cells through CD 1‐restricted receptors for α‐ G alCer 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 CD 1, inducible NOS ( iNOS ), CD 95 and IFN ‐γ, along with the effects of lymphocytes; IFN ‐γ; caspase and iNOS inhibitors; non‐steroidal anti‐inflammatory drugs ( NSAIDs ) and LTD 4 ; and dexamethasone. Key Results α‐GalCer (10 −6 –10 −8 M) 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 , CD 95, CD 28; or CD 1d. Separation on Percoll gradients and depletion of CD 3+ 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 CD 1d‐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 LTD 4 and NSAID s.Conclusions and Implications α‐ GalCer activation of IFN ‐γ‐secreting, CD 1d‐restricted lymphocytes induced iNOS ‐ CD 95‐dependent apoptosis in developing eosinophils. This pathway is initiated by endogenous regulatory lymphocytes, antagonised by LTD 4 , NSAIDs and aminoguanidine, and modified by dexamethasone.