Blockage of Eosinopoiesis by IL-17A Is Prevented by Cytokine and Lipid Mediators of Allergic Inflammation

• Published in: Mediators of Inflammation 2015-01, Vol.2015 (2015), p.1124-1134-503
• Main Authors: Xavier-Elsas, Pedro, de Luca, Bianca, Queto, Túlio, Vieira, Bruno Marques, Masid-de-Brito, Daniela, Dahab, Elizabeth Chen, Alves Filho, José Carlos, Cunha, Fernando Q., Gaspar-Elsas, Maria Ignez C.
• Format: Article
• Language: English
• Subjects: Allergies; Animals; Asthma; Bone marrow; Cell Differentiation - drug effects; Cytokines; Cytokines - pharmacology; Eosinophils - drug effects; Eosinophils - metabolism; Female; Health aspects; Hypersensitivity - drug therapy; Inflammation; Inflammation - metabolism; Interleukin-13 - pharmacology; Interleukin-17 - pharmacology; Interleukin-4 - pharmacology; Interleukin-5 - pharmacology; Interleukins; Lipids; Male; Mice; Mice, Inbred BALB C; Neutrophils; Physiological aspects; Studies; Womens health
• ISSN: 0962-9351; 1466-1861
• DOI: 10.1155/2015/968932

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.