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2015 ; 2015
(ä): 968932
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Blockage of Eosinopoiesis by IL-17A Is Prevented by Cytokine and Lipid Mediators
of Allergic Inflammation
#MMPMID26199466
Xavier-Elsas P
; de Luca B
; Queto T
; Vieira BM
; Masid-de-Brito D
; Dahab EC
; Alves Filho JC
; Cunha FQ
; Gaspar-Elsas MI
Mediators Inflamm
2015[]; 2015
(ä): 968932
PMID26199466
show ga
Interleukin- (IL-) 17A, a pleiotropic mediator of inflammation and autoimmunity,
potently stimulates bone-marrow neutrophil production. To explore IL-17A effects
on eosinopoiesis, we cultured bone-marrow from wild-type mice, or mutants lacking
inducible nitric oxide synthase (iNOS-/-), CD95 (lpr), IL-17RA, or IL-4, with
IL-5, alone or associated with IL-17A. Synergisms between IL-17A-activated,
NO-dependent, and NO-independent mechanisms and antagonisms between IL-17A and
proallergic factors were further examined. While IL-17A (0.1-10?ng/mL) had no
IL-5-independent effect on eosinopoiesis, it dose-dependently suppressed
IL-5-induced eosinophil differentiation, by acting during the initial 24 hours.
Its effectiveness was abolished by caspase inhibitor, zVAD-fmk. The effect of
IL-17A (0.1-1?ng/mL) was sensitive to the iNOS-selective inhibitor aminoguanidine
and undetectable in iNOS-/- bone-marrow. By contrast, a higher IL-17A
concentration (10?ng/mL) retained significant suppressive effect in both
conditions, unmasking a high-end iNOS-independent mechanism. Lower IL-17A
concentrations synergized with NO donor nitroprusside. Eosinopoiesis suppression
by IL-17A was (a) undetectable in bone-marrow lacking IL-17RA or CD95 and (b)
actively prevented by LTD4, LTC4, IL-13, and eotaxin. Sensitivity to IL-17A was
increased in bone-marrow lacking IL-4; adding IL-4 to the cultures restored IL-5
responses to control levels. Therefore, effects of both IL-17A and proallergic
factors are transduced by the iNOS-CD95 pathway in isolated bone-marrow.