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IL-36? exerts pro-inflammatory effects in the lungs of mice.

ABSTRACT: Interleukin (IL-) 36 cytokines (previously designated as novel IL-1 family member cytokines; IL-1F5- IL-1F10) constitute a novel cluster of cytokines structurally and functionally similar to members of the IL-1 cytokine cluster. The effects of IL-36 cytokines in inflammatory lung disorders remains poorly understood. The current study sought to investigate the effects of IL-36? (IL-1F6) and test the hypothesis that IL-36? acts as a pro-inflammatory cytokine in the lung in vivo. Intratracheal instillation of recombinant mouse IL-36? induced neutrophil influx in the lungs of wild-type C57BL/6 mice and IL-1??(-/-) mice in vivo. IL-36? induced neutrophil influx was also associated with increased mRNA expression of neutrophil-specific chemokines CXCL1 and CXCL2 in the lungs of C57BL/6 and IL-1??(-/-) mice in vivo. In addition, intratracheal instillation of IL-36? enhanced mRNA expression of its receptor IL-36R in the lungs of C57BL/6 as well as IL-1??(-/-) mice in vivo. Furthermore, in vitro incubation of CD11c(+) cells with IL-36? resulted in the generation of neutrophil-specific chemokines CXCL1, CXCL2 as well as TNF?. IL-36? increased the expression of the co-stimulatory molecule CD40 and enhanced the ability of CD11c(+) cells to induce CD4(+) T cell proliferation in vitro. Furthermore, stimulation with IL-36? activated NF-?B in a mouse macrophage cell line. These results demonstrate that IL-36? acts as a pro-inflammatory cytokine in the lung without the contribution of IL-1? and IL-1?. The current study describes the pro-inflammatory effects of IL-36? in the lung, demonstrates the functional redundancy of IL-36? with other agonist cytokines in the IL-1 and IL-36 cytokine cluster, and suggests that therapeutic targeting of IL-36 cytokines could be beneficial in inflammatory lung diseases.

SUBMITTER: Ramadas RA

PROVIDER: S-EPMC3447790 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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IL-36α exerts pro-inflammatory effects in the lungs of mice.

Ramadas Ravisankar A RA Ewart Susan L SL Iwakura Yoichiro Y Medoff Benjamin D BD LeVine Ann Marie AM

PloS one 20120920 9

Interleukin (IL-) 36 cytokines (previously designated as novel IL-1 family member cytokines; IL-1F5- IL-1F10) constitute a novel cluster of cytokines structurally and functionally similar to members of the IL-1 cytokine cluster. The effects of IL-36 cytokines in inflammatory lung disorders remains poorly understood. The current study sought to investigate the effects of IL-36α (IL-1F6) and test the hypothesis that IL-36α acts as a pro-inflammatory cytokine in the lung in vivo. Intratracheal inst ...[more]

PMID: 23029241

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Project description:ObjectiveProtein Z (PZ) is a vitamin K-dependent coagulation factor without catalytic activity. Evidence points towards PZ as an independent risk factor for the occurrence of human peripheral arterial disease. However, the role of PZ in ischemia-driven angiogenesis and vascular healing processes has not been elucidated so far.ApproachAngiogenic potency of PZ was assessed in established in vitro assays using endothelial cells. PZ-deficient (PZ(-/-)) mice and their wild-type littermates (PZ(+/+)) were subjected to hindlimb ischemia. Furthermore, PZ(-/-) mice were exposed to PZ expressing adenovirus (AdV-PZ) or control adenovirus (AdV-GFP). In an additional set of animals, PZ(-/-) mice were exposed to AdV-PZ and AdV-GFP, each in combination with the CXCR4 antagonist AMD3100.ResultsIn vitro, PZ stimulated migratory activity and capillary-like tube formation of endothelial cells comparable to SDF-1. PZ(-/-) mice exhibited diminished hypoxia-driven neovascularization and reperfusion in post-ischemic hindlimbs, which was restored by adenoviral gene transfer up to levels seen in PZ(+/+) mice. The stimulatory impact of PZ on endothelial cells in vitro was abolished by siRNA targeting against PZ and PZ was not able to restore reduced migration after knock-down of CXCR4. The increased surface expression of CXCR4 on PZ-stimulated endothelial cells and the abrogated restoration of PZ(-/-) mice via AdV-PZ after concomitant treatment with the CXCR4 antagonist AMD3100 supports the idea that PZ mediates angiogenesis via a G-protein coupled pathway and involves the SDF-1/CXCR4 axis. This is underlined by the fact that addition of the G-protein inhibitor PTX to PZ-stimulated endothelial cells abolished the effect of PZ on capillary-like tube formation.ConclusionsThe results of the current study reveal a role of PZ in ischemia-induced angiogenesis, which involves a G-protein coupled pathway and a raised surface expression of CXCR4. Our findings thereby extend the involvement of PZ from the coagulation cascade to a beneficial modulation of vascular homeostasis.

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IL-36? exerts pro-inflammatory effects in the lungs of mice.

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IL-36α exerts pro-inflammatory effects in the lungs of mice.

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