Cytokine-induced injury of the lacrimal and salivary glands
Cytokine-induced injury of the lacrimal and salivary glands
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DOI：
10.1097/00002371-200203001-00007
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发表时间：
2002-03-01
影响因子：
3.9
通讯作者：
Okamura, H
中科院分区：
文献类型：
--
作者：
Kimura-Shimmyo, A;Kashiwamura, SI;Okamura, H
伴随各种自身免疫性疾病的泪腺和唾液腺损伤被归类为继发性干燥综合征。细胞因子和自由基被认为是导致病理变化的原因，但其确切机制尚不清楚。我们评估了细胞因子单独是否可以引起这些外分泌组织的损伤，以及气体分子如一氧化氮（NO）是否在这些损伤中起作用。将各种敲除（KO）小鼠以及野生型小鼠腹膜内（i. p.）与促炎细胞因子IL-12和IL-18单独或组合。对小鼠同时施用IL-12和IL-18引起泪腺和唾液腺严重萎缩，当单独施用每种细胞因子时，泪腺和唾液腺免于萎缩。显微镜下，没有明显的浸润细胞，然而，在上皮中观察到大量凋亡细胞，这通过凝胶电泳上DNA梯状条带的形成来证实。血清IFN-γ和NO2/NO3水平明显升高。联合注射IL-12和IL-18在Fas缺陷和Fas配体缺陷小鼠中引起相同的变化。以及在穿孔素-KO小鼠中，但在诱导型NO转移酶-KO小鼠或IFN-γ KO小鼠中未检测到相同的变化。因此，IL-12和IL-18的协同作用依赖于IFN-γ和NO的产生，而不依赖于Fas/Fas配体系统和穿孔素依赖性细胞毒性T细胞。IL-18和IL-12一起引起腺体组织的破坏性变化，但没有明显的淋巴细胞浸润。提示这些细胞因子可介导腺上皮细胞的凋亡，而NO产生的增加是导致这种变化的原因。
Damages to the lacrimal and salivary glands that accompany various autoimmune diseases are categorized as secondary Sjogren syndrome. Cytokines and free radicals are thought to be responsible for the pathologic changes, but the precise mechanisms are not clear. We evaluated whether cytokines alone can cause the damages in these exocrine tissues, and whether gaseous molecules such as nitric oxide (NO) play a role in these injuries. Various knockout (KO) mice as well as wild-type mice were injected intraperitoneally (i.p.) with the proinflammatory cytokines, IL-12 and IL-18, singly or in combination. Concurrent administration of IL-12 and IL-18 to mice caused serious atrophy in the lacrimal and salivary glands, which was spared when each cytokine was singly administered. Microscopically, there were apparently no infiltrating cells, nonetheless, numerous apoptotic cells were observed in the epithelium, which was confirmed by DNA ladder formation on gel electrophoresis. Serum levels of IFN-gamma and NO2/NO3 were markedly elevated. Combined injections of IL-12 and IL-18 caused the same changes in Fas-deficient and Fas-ligand deficient mice. as well as in perforin-KO mice, but the same changes were not detected in inducible NO synthase-KO mice or IFN-gamma KO mice. Thus, the synergistic effect of IL-12 and IL-18 was dependent on production of IFN-gamma and NO, but independent of Fas/Fas ligand system and perforin-dependent cytotoxic T cells. IL-18 together with IL-12 caused destructive changes in the glandular tissues without apparent lymphocyte infiltration. It is suggested that these cytokines can mediate apoptosis in glandular epithelial cells and that the elevated NO production is responsible for the change.