Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level of IL-18
Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level of IL-18
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DOI：
10.4049/jimmunol.165.2.997
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发表时间：
2000-07-15
影响因子：
4.4
通讯作者：
Mizutani, H
中科院分区：
文献类型：
--
作者：
Yamanaka, K;Tanaka, M;Mizutani, H
为了研究过度表达的半胱天冬酶-1（CASP 1）（最初称为IL-1 β转化酶）的病理生理作用，我们产生了转基因小鼠，其中人CASP 1在其角质形成细胞中过度表达。转基因小鼠自发地发展为湿疹性皮炎和皮肤溃疡，其特征在于存在大量角质形成细胞凋亡。小鼠的皮肤含有人CASP 1的活性形式，并表达半胱天冬酶激活的DNA酶的mRNA，这是一种负责DNA片段化的效应内切酶。他们的皮肤和血清显示成熟IL-18和IL-1 β水平升高，但IFN-γ水平没有升高。来自这些动物的血浆通过IL-1 s-应答性NK细胞诱导IFN-γ产生。施用热灭活的痤疮丙酸杆菌（一种有效的体内1型细胞诱导剂）在转基因小鼠中引起IFN-γ介导的致死性肝损伤，其被中和抗IL-18 Ab治疗完全抑制，这些结果表明，体内CASP 1的过表达引起自发性凋亡组织损伤，并使小鼠对外源性1型细胞高度敏感。诱导条件与内源性积累的促炎细胞因子合作。
To study the pathophysiological roles of overexpressed caspase-1 (CASP1), originally designated as IL-1 beta-converting enzyme, we generated transgenic mice in which human CASP1 is overexpressed in their keratinocytes. The transgenic mice spontaneously developed recalcitrant dermatitis and skin ulcers, characterized by the presence of massive keratinocyte apoptosis, The skin of the mice contained the active form of human CASP1 and expressed mRNA for caspase-activated DNase, an effector endonuclease responsible for DNA fragmentation. Their skin and sera showed elevated levels of mature IL-18 and IL-1 beta, but not of IFN-gamma. The plasma from these animals induced IFN-gamma production by IL-ls-responsive NK cells. Administration of heat-killed Propionibacterium acnes, a potent in vivo type 1 cell inducer, caused IFN-gamma-mediated lethal liver injury in the transgenic mice, which was completely inhibited by treatment with neutralizing anti-IL-18 Ab, These results indicated that in vivo overexpression of CASP1 caused spontaneous apoptotic tissue injury and rendered mice highly susceptible to exogenous type 1 cell-inducing condition in collaboration with endogenously accumulated proinflammatory cytokines.