Amar S, Van Dyke T E, Eugster H P, Schultze N, Koebel P, Bluethmann H
Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University, Massachusetts 02118, USA.
J Inflamm. 1995;47(4):180-9.
Tumor necrosis factor (TNF) is a central mediator of immune and inflammatory responses. Its activities have been shown to be mediated by two distinct receptors, TNFR1 (p55) and TNFR2 (p75). The cytoplasmic domains of both TNF receptors are unrelated, suggesting that they link to different intracellular signaling pathways. To determine their role in vivo in lipopolysaccharide (LPS)- and TNF-induced skin inflammatory necrosis, TNFR1-, TNFR2-, and TNF lymphotoxin-alpha (LT alpha)-deficient mice were used. Skin abscesses were experimentally induced with local application of TNF or LPS. Large macroscopic ulcerations were observed in TNF-injected wild-type animals and to a slightly lesser extent in TNFR2-deficient mice with tissue destruction in both cases extending deep into the dermis. Tissue destruction was accompanied by an intense immune infiltrate composed mainly of neutrophils, lymphocytes, and macrophages. TNFR1-deficient and TNFR1/TNFR2-double-deficient mice, however, did not exhibit any ulceration and showed only a very mild inflammatory infiltrate. In TNF/LT alpha-double ligand0-deficient animals, a moderate epidermal necrosis was observed with a reduced inflammatory infiltrate compared to wild-type animals. As with TNF injections, subcutaneous injection of LPS induced a comparable pattern of skin necrosis in wild-type and TNF receptor mutant mice, yet a slightly more acute inflammatory level was observed regardless of the type of animal tested. As found for TNF-induced skin necrosis, the extent of LPS-induced skin necrosis was reduced in TNF/LT alpha-deficient mice compared to wild-type animals. The present data strongly suggest that TNFR1, rather than TNFR2, is engaged in LPS- and TNF-induced skin necrosis and highlight the predominant role played by TNF in LPS-induced inflammatory diseases.
肿瘤坏死因子（TNF）是免疫和炎症反应的核心介质。其活性已被证明是由两种不同的受体介导的，即TNFR1（p55）和TNFR2（p75）。两种TNF受体的胞质结构域不相关，这表明它们与不同的细胞内信号通路相连。为了确定它们在体内对脂多糖（LPS）和TNF诱导的皮肤炎性坏死中的作用，使用了TNFR1、TNFR2和TNF淋巴毒素α（LTα）缺陷型小鼠。通过局部应用TNF或LPS实验性诱导皮肤脓肿。在注射TNF的野生型动物中观察到大面积的肉眼可见溃疡，在TNFR2缺陷型小鼠中程度稍轻，两种情况下组织破坏均深入真皮层。组织破坏伴随着主要由中性粒细胞、淋巴细胞和巨噬细胞组成的强烈免疫浸润。然而，TNFR1缺陷型和TNFR1/TNFR2双缺陷型小鼠未出现任何溃疡，仅表现出非常轻微的炎性浸润。在TNF/LTα双配体缺陷型动物中，观察到中度表皮坏死，与野生型动物相比炎性浸润减少。与注射TNF一样，皮下注射LPS在野生型和TNF受体突变型小鼠中诱导出类似的皮肤坏死模式，但无论测试的动物类型如何，均观察到稍高的急性炎症水平。正如在TNF诱导的皮肤坏死中所发现的，与野生型动物相比，TNF/LTα缺陷型小鼠中LPS诱导的皮肤坏死程度降低。目前的数据强烈表明，TNFR1而非TNFR2参与了LPS和TNF诱导的皮肤坏死，并突出了TNF在LPS诱导的炎症性疾病中所起的主要作用。
