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Invariant NKT cell activation induces neutrophil accumulation and hepatitis: opposite regulation by IL-4 and IFN-?.

ABSTRACT: UNLABELLED:Alpha-Galactosylceramide (?-Galcer), a specific agonist for invariant natural killer T (iNKT) cells, is being evaluated in clinical trials for the treatment of viral hepatitis and liver cancer. However, the results from ?-Galcer treatment are mixed, partially because of the variety of cytokines produced by activated iNKT cells that have an unknown synergistic effect on the progression of liver disease. It is well documented that injection of ?-Galcer induces mild hepatitis with a rapid elevation in the levels of interleukin (IL)-4 and a delayed elevation in the levels of interferon-gamma (IFN-?), and both of these cytokines are thought to mediate many functions of iNKT cells. Surprisingly, genetic deletion of both IL-4 and IFN-? aggravated, rather than abolished, ?-Galcer-induced iNKT hepatitis. Moreover, genetic ablation of IL-4, the IL-4 receptor, or its downstream signaling molecule signal transducer and activator of transcription (STAT)6 ameliorated ?-Galcer-induced neutrophil infiltration, liver injury, and hepatitis. In contrast, genetic deletion of IFN-?, the IFN-? receptor, or its downstream signaling molecule STAT1 enhanced liver neutrophil accumulation, thereby exacerbating liver injury and hepatitis. Moreover, depletion of neutrophils eradicated ?-Galcer-induced liver injury in wild-type, STAT1 knockout, and IFN-? knockout mice. CONCLUSION:Our results propose a model in which activated iNKT cells rapidly release IL-4, which promotes neutrophil survival and hepatitis but also sequentially produce IFN-?, which acts in a negative feedback loop to ameliorate iNKT hepatitis by inducing neutrophil apoptosis. Thus, modification of iNKT production of IL-4 and IFN-? may have the potential to improve the efficacy of ?-Galcer in the treatment of liver disease.

SUBMITTER: Wang H

PROVIDER: S-EPMC3758807 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Invariant NKT cell activation induces neutrophil accumulation and hepatitis: opposite regulation by IL-4 and IFN-γ.

Wang Hua H Feng Dechun D Park Ogyi O Yin Shi S Gao Bin B

Hepatology (Baltimore, Md.) 20130806 4

<h4>Unlabelled</h4>Alpha-Galactosylceramide (α-Galcer), a specific agonist for invariant natural killer T (iNKT) cells, is being evaluated in clinical trials for the treatment of viral hepatitis and liver cancer. However, the results from α-Galcer treatment are mixed, partially because of the variety of cytokines produced by activated iNKT cells that have an unknown synergistic effect on the progression of liver disease. It is well documented that injection of α-Galcer induces mild hepatitis wit ...[more]

PMID: 23686838

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Project description:Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. Although intra-amniotic infection is a recognized cause of spontaneous preterm labor, the noninfection-related etiologies are poorly understood. In this article, we demonstrated that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of ?-galactosylceramide (?-GalCer) induced late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent ?-GalCer-induced late PTB had bradycardia and died shortly after delivery. Yet, administration of ?-GalCer in the second trimester did not cause pregnancy loss. Peroxisome proliferator-activated receptor (PPAR)? activation, through rosiglitazone treatment, reduced the rate of ?-GalCer-induced late PTB and improved neonatal survival. Administration of ?-GalCer in the third trimester suppressed PPAR? activation, as shown by the downregulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of ?-GalCer in the third trimester induced an increase in the activation of conventional CD4(+) T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils, and mature dendritic cells to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of ?-GalCer also upregulated the expression of inflammatory genes at the maternal-fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT-like cells in human decidual tissues is associated with noninfection-related preterm labor/birth. Collectively, these results demonstrate that iNKT cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPAR? pathway has potential as a target for prevention of this syndrome.

Dataset Information

Invariant NKT cell activation induces neutrophil accumulation and hepatitis: opposite regulation by IL-4 and IFN-?.

Publications

Invariant NKT cell activation induces neutrophil accumulation and hepatitis: opposite regulation by IL-4 and IFN-γ.

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