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Il-36 Cytokines Are Required for Effective Host Defense Against Murine Legionella Pneumophila Pneumonia
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A7576 - Il-36 Cytokines Are Required for Effective Host Defense Against Murine Legionella Pneumophila Pneumonia
Author Block: Y. Nanjo1, M. W. Newstead1, T. Aoyagi2, X. Zeng1, K. Takahashi3, K. Tateda4, T. J. Standiford1; 1University of Michigan, Ann Arbor, MI, United States, 2Tohoku University, Sendai, Japan, 3Juntendo University, Tokyo, Japan, 4Toho University, Tokyo, Japan.
[Rational] Interleukin (IL)-36 cytokines are member of the IL-1 cytokine family. The IL-36 cytokines IL-36α, IL-36β and IL-36γ bind to IL-36 receptor (IL-36R-/-) and IL-1RAcP. Although these proteins are known exert potent inflammatory effects, little is known regarding IL-36 cytokines in host defense against pneumonia. Therefore, the objective of this study was to examine the role of IL-36 cytokines in Legionella pneumonia.
[Methods] 107 CFU of L. pneumophila (Lp, Suzuki strain) was administrated intratracheally to C57BL/6 wild-type (WT), IL-36R (IL-36R-/-) deficient. At 2 and 4 post infection days, bronchoalveolar lavage (BAL) was performed, and lungs were harvested. BAL fluid was examined for quantitation of leukocytes and albumin. Lung tissue was cultured for bacterial CFU determination. For in vitro studies, mouse primary pulmonary macrophages (PMs) isolated from WT mice and IL-36R-/- mice were examined for intracellular bacterial killing and production of IL-36 cytokines.
[Results] Administration of Lp in WT mice resulted in upregulation of both IL-36α and IL-36γ mRNA and protein production in lung by 2 days post infection. Mortality of IL-36R-/- mice after bacterial challenge was significantly higher than that of WT mice. Lp CFU in lungs in IL-36R-/- were not significantly difference compared with WT at day 2, but were significantly increased at day 4 and day 6. At day 2 and 4, inflammatory cells in BAL were reduced in infected IL-36R-/- mice as compared to WT controls. In vitro, impaired intracellular killing of Lp was observed in PMs isolated from IL-36R-/- WT mice. Interestingly, redundancy of IL-36 agonist effects was observed, as no increased lethality was observed in IL-36α or IL-36γ deficient mice, whereas antibody mediated neutralization of IL-36γ in IL-36α-/- mice resulted in increased mortality approximating that observed in IL-36R-/- animals.
[Conclusion] Our studies indicate that defects in IL-36R signaling results in impaired bacterial clearance, reduced inflammatory cells influx, and increased mortality during murine Legionella pneumonia.
This abstract is funded by: National Institutes of Health/National Heart Lung, and Blood Institute Grants NIH/NHLBI R01 HL123515 and R01 HL097564 (TJS)
Author Block: Y. Nanjo1, M. W. Newstead1, T. Aoyagi2, X. Zeng1, K. Takahashi3, K. Tateda4, T. J. Standiford1; 1University of Michigan, Ann Arbor, MI, United States, 2Tohoku University, Sendai, Japan, 3Juntendo University, Tokyo, Japan, 4Toho University, Tokyo, Japan.
[Rational] Interleukin (IL)-36 cytokines are member of the IL-1 cytokine family. The IL-36 cytokines IL-36α, IL-36β and IL-36γ bind to IL-36 receptor (IL-36R-/-) and IL-1RAcP. Although these proteins are known exert potent inflammatory effects, little is known regarding IL-36 cytokines in host defense against pneumonia. Therefore, the objective of this study was to examine the role of IL-36 cytokines in Legionella pneumonia.
[Methods] 107 CFU of L. pneumophila (Lp, Suzuki strain) was administrated intratracheally to C57BL/6 wild-type (WT), IL-36R (IL-36R-/-) deficient. At 2 and 4 post infection days, bronchoalveolar lavage (BAL) was performed, and lungs were harvested. BAL fluid was examined for quantitation of leukocytes and albumin. Lung tissue was cultured for bacterial CFU determination. For in vitro studies, mouse primary pulmonary macrophages (PMs) isolated from WT mice and IL-36R-/- mice were examined for intracellular bacterial killing and production of IL-36 cytokines.
[Results] Administration of Lp in WT mice resulted in upregulation of both IL-36α and IL-36γ mRNA and protein production in lung by 2 days post infection. Mortality of IL-36R-/- mice after bacterial challenge was significantly higher than that of WT mice. Lp CFU in lungs in IL-36R-/- were not significantly difference compared with WT at day 2, but were significantly increased at day 4 and day 6. At day 2 and 4, inflammatory cells in BAL were reduced in infected IL-36R-/- mice as compared to WT controls. In vitro, impaired intracellular killing of Lp was observed in PMs isolated from IL-36R-/- WT mice. Interestingly, redundancy of IL-36 agonist effects was observed, as no increased lethality was observed in IL-36α or IL-36γ deficient mice, whereas antibody mediated neutralization of IL-36γ in IL-36α-/- mice resulted in increased mortality approximating that observed in IL-36R-/- animals.
[Conclusion] Our studies indicate that defects in IL-36R signaling results in impaired bacterial clearance, reduced inflammatory cells influx, and increased mortality during murine Legionella pneumonia.
This abstract is funded by: National Institutes of Health/National Heart Lung, and Blood Institute Grants NIH/NHLBI R01 HL123515 and R01 HL097564 (TJS)
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