IFN-γ protects cerulein-induced acute pancreatitis by repressing NF-κB activation
IFN-γ protects cerulein-induced acute pancreatitis by repressing NF-κB activation
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DOI：
10.4049/jimmunol.178.11.7385
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发表时间：
2007-06-01
影响因子：
4.4
通讯作者：
Kondo, Toshikazu
中科院分区：
文献类型：
--
作者：
Hayashi, Takahito;Ishida, Yuko;Kondo, Toshikazu
我们探讨了IFN-γ在蛙皮素诱导的急性胰腺炎中的病理生理作用。在野生型（WT）小鼠中，蛙皮素注射引起急性胰腺炎，表现为血清淀粉酶水平升高和胰腺间质水肿、空泡化、腺泡细胞坏死和中性粒细胞浸润等病理变化。同时，雨蛙肽治疗增加了WT小鼠胰腺内TNF-α、KC/CXCL 1、MIP-2/CXCL 2、环氧合酶-2（考克斯-2）和IFN-γ的基因表达。原位杂交结合免疫荧光分析表明，浸润的中性粒细胞表达IFN-γ mRNA。出乎意料的是，IFN-γ（-/-）小鼠表现出加重的雨蛙素诱导的胰腺损伤，并伴有增强的中性粒细胞募集。此外，与WT小鼠相比，IFN-γ（-/-）小鼠中TNF-α、KC/CXCL 1、MIP-2/CXCL 2和考克斯-2的胰腺内基因表达显著增加。蛙皮素激活NF-κ B，NF-κ B是蛙皮素处理的WT小鼠胰腺中TNF-α、KC/CXCL 1、MIP-2/CXCL 2和考克斯-2基因转录不可或缺的转录因子，这一点通过NF-κ B p65的核量和DNA结合活性增加得到证明。与WT小鼠相比，IFN-γ（-/-）小鼠表现出过度和延长的NF-κ B活化，这可能是由于IFN-γ的主要信号转导子Stat 1的乙酰化减少，因为乙酰化的Stall可以抑制NF-κ B活化。事实上，IFN-γ乙酰化的Stat 1和STAT 3减少了中性粒细胞中NF-κ B的激活和考克斯-2的表达。最后，即使在第一次注射雨蛙肽后4小时给药，IFN-γ在WT和IFN-γ（-/-）小鼠中均显著减轻急性胰腺炎，并降低NF-κ B活化和考克斯-2表达。因此，IFN-γ可通过抑制NF-κ B活化的促炎性结果而对急性胰腺炎具有抗炎作用。
We explored the pathophysiological roles of IFN-gamma in cerulein-induced acute pancreatitis. In wild-type (WT) mice, cerulein injection caused acute pancreatitis as evidenced by increased serum amylase levels and pathological changes such as interstitial edema, vacuolization, acinar cell necrosis, and neutrophil infiltration in pancreas. Concomitantly, cerulein treatment augmented intrapancreatic gene expression of TNF-alpha, KC/CXCL1, MIP-2/CXCL2, cyclooxygenase-2 (COX-2), and IFN-gamma in WT mice. In situ hybridization combined with immunofluorescence analyses demonstrated that infiltrating neutrophils expressed IFN-gamma mRNA. Unexpectedly, IFN-gamma(-/-) mice exhibited exacerbated cerulein-induced pancreatic injury, with enhanced neutrophil recruitment. Moreover, intrapancreatic gene expression of TNF-a, KC/CXCL1, MIP-2/CXCL2, and COX-2 were significantly exaggerated in IFN-gamma(-/-) mice, compared with WT mice. Cerulein activated NF-kappa B, an indispensable transcription factor for gene transcription of TNF-alpha, KC/CXCL1, MIP-2/CXCL2, and COX-2, in pancreas of cerulein-treated WT mice as evidenced by the increases in nuclear amount and DNA-binding activity of NF-kappa B p65. In comparison with WT mice, IFN-gamma(-/-) mice exhibited exaggerated and prolonged NF-kappa B activation, probably due to reduced acetylation of Stat1, a main signal transducer of IFN-gamma, because acetylated Stall can inhibit NF-kappa B activation. Indeed, IFN-gamma acetylated Stat1 and reciprocally reduced NF-kappa B activation and COX-2 expression in neutrophils. Finally, even when administered 4 h after the first cerulein injection, IFN-gamma remarkably attenuated acute pancreatitis in both WT and IFN-gamma(-/-) mice, with reduced NF-kappa B activation and COX-2 expression. Thus, IFN-gamma can have anti-inflammatory effects on acute pancreatitis by depressing the proinflammatory consequences of NF-kappa B activation.