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

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)

Bottom Line: 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.By contrast, a higher IL-17A concentration (10 ng/mL) retained significant suppressive effect in both conditions, unmasking a high-end iNOS-independent mechanism.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Paulo de Góes Institute for Microbiology, Federal University of Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, RJ, Brazil.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Blockade of IL-17 effects by agents which signal through CysLT1R. Liquid bone-marrow cultures were established from BALB/c mice as detailed in Figure 1. Different agonists which share the ability to signal through CysLT type 1 receptors (CysLT1R) were added to the cultures, alone or in association with IL-17A. These include (a) IL-13 and (b) eotaxin (Eot) [36] and (c) leukotriene D4 (LTD4) and (d) indomethacin [34]. ∗P < 0.05 for the indicated differences. Data are mean ± SEM (n = 3).
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fig4: Blockade of IL-17 effects by agents which signal through CysLT1R. Liquid bone-marrow cultures were established from BALB/c mice as detailed in Figure 1. Different agonists which share the ability to signal through CysLT type 1 receptors (CysLT1R) were added to the cultures, alone or in association with IL-17A. These include (a) IL-13 and (b) eotaxin (Eot) [36] and (c) leukotriene D4 (LTD4) and (d) indomethacin [34]. ∗P < 0.05 for the indicated differences. Data are mean ± SEM (n = 3).

Mentions: Because the common biochemical mechanism shared by these heterogeneous agents was known to prevent suppression by PGE2, we further examined whether IL-13, eotaxin, LTD4, and indomethacin would be equally effective in blocking the actions of IL-17A (Figure 4). Consistently with this hypothesis, both IL-13 (Figure 4(a)) and eotaxin (Figure 4(b)) prevented suppression of eosinopoiesis by IL-17A, in addition to enhancing eosinopoiesis in the absence of IL-17A. LTD4, 10−8 M, abolished the suppressive effect of IL-17A, 1 ng/mL (Figure 4(c)), in addition to enhancing eosinopoiesis in the absence of IL-17A. Similar observations were made with LTC4 (not shown). Finally (Figure 4(d)), indomethacin was able to enhance eosinopoiesis and to block the effect of IL-17A. In all cases, blockade by all four agents brought eosinophil production back to the IL-5 control levels.


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

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)

Blockade of IL-17 effects by agents which signal through CysLT1R. Liquid bone-marrow cultures were established from BALB/c mice as detailed in Figure 1. Different agonists which share the ability to signal through CysLT type 1 receptors (CysLT1R) were added to the cultures, alone or in association with IL-17A. These include (a) IL-13 and (b) eotaxin (Eot) [36] and (c) leukotriene D4 (LTD4) and (d) indomethacin [34]. ∗P < 0.05 for the indicated differences. Data are mean ± SEM (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4493302&req=5

fig4: Blockade of IL-17 effects by agents which signal through CysLT1R. Liquid bone-marrow cultures were established from BALB/c mice as detailed in Figure 1. Different agonists which share the ability to signal through CysLT type 1 receptors (CysLT1R) were added to the cultures, alone or in association with IL-17A. These include (a) IL-13 and (b) eotaxin (Eot) [36] and (c) leukotriene D4 (LTD4) and (d) indomethacin [34]. ∗P < 0.05 for the indicated differences. Data are mean ± SEM (n = 3).
Mentions: Because the common biochemical mechanism shared by these heterogeneous agents was known to prevent suppression by PGE2, we further examined whether IL-13, eotaxin, LTD4, and indomethacin would be equally effective in blocking the actions of IL-17A (Figure 4). Consistently with this hypothesis, both IL-13 (Figure 4(a)) and eotaxin (Figure 4(b)) prevented suppression of eosinopoiesis by IL-17A, in addition to enhancing eosinopoiesis in the absence of IL-17A. LTD4, 10−8 M, abolished the suppressive effect of IL-17A, 1 ng/mL (Figure 4(c)), in addition to enhancing eosinopoiesis in the absence of IL-17A. Similar observations were made with LTC4 (not shown). Finally (Figure 4(d)), indomethacin was able to enhance eosinopoiesis and to block the effect of IL-17A. In all cases, blockade by all four agents brought eosinophil production back to the IL-5 control levels.

Bottom Line: 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.By contrast, a higher IL-17A concentration (10 ng/mL) retained significant suppressive effect in both conditions, unmasking a high-end iNOS-independent mechanism.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Paulo de Góes Institute for Microbiology, Federal University of Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, RJ, Brazil.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus