Tartaglia L A, Weber R F, Figari I S, Reynolds C, Palladino M A, Goeddel D V
Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080.
Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9292-6. doi: 10.1073/pnas.88.20.9292.
The individual roles of the murine type 1 and type 2 tumor necrosis factor (TNF) receptors (TNF-R1 and TNF-R2) were investigated utilizing (i) the strong species specificity of TNF-R2 for murine TNF compared to human TNF and (ii) agonistic rabbit polyclonal antibodies directed against the individual TNF receptors. Proliferation of mouse thymocytes and the murine cytotoxic T-cell line CT-6 is stimulated by murine TNF but not by human TNF. Consistent with this observation, polyclonal antibodies directed against TNF-R2 induced proliferation in both of these cell types, whereas polyclonal antibodies directed against TNF-R1 had no effect. In contrast, cytotoxicity in murine LM cells (which are sensitive to murine and human TNF) was induced by antibodies against TNF-R1 but not by antibodies against TNF-R2. Also, the steady-state level of manganous superoxide dismutase mRNA in the murine NIH 3T3 cell line was induced by murine TNF, human TNF, and anti-TNF-R1 but not by anti-TNF-R2. These results suggest that TNF-R2 initiates signals for the proliferation of thymocytes and cytotoxic T cells, whereas TNF-R1 initiates signals for cytotoxicity and the induction of the protective activity, manganous superoxide dismutase. The nonredundant signaling observed for the two TNF receptors cannot be explained simply by the differential expression of the two TNF receptors in the various cell types, because LM cells express on their surface higher levels of TNF-R2 than TNF-R1, and LM cells, NIH 3T3 cells, and thymus cells all express mRNA corresponding to both receptor types. It is therefore likely that the two receptors initiate distinct signaling pathways that result in the induction of different cellular responses.
利用（i）与人类肿瘤坏死因子（TNF）相比，TNF-R2对鼠TNF具有很强的物种特异性，以及（ii）针对单个TNF受体的激动性兔多克隆抗体，研究了小鼠1型和2型肿瘤坏死因子受体（TNF-R1和TNF-R2）的个体作用。小鼠TNF可刺激小鼠胸腺细胞和小鼠细胞毒性T细胞系CT-6的增殖，但人类TNF则无此作用。与该观察结果一致，针对TNF-R2的多克隆抗体可诱导这两种细胞类型的增殖，而针对TNF-R1的多克隆抗体则无作用。相反，针对TNF-R1的抗体可诱导鼠LM细胞（对鼠和人类TNF敏感）产生细胞毒性，而针对TNF-R2的抗体则无此作用。此外，鼠NIH 3T3细胞系中锰超氧化物歧化酶mRNA的稳态水平可由鼠TNF、人类TNF和抗TNF-R1诱导，但不能由抗TNF-R2诱导。这些结果表明，TNF-R2启动胸腺细胞和细胞毒性T细胞增殖的信号，而TNF-R1启动细胞毒性和保护性活性（锰超氧化物歧化酶）诱导的信号。两种TNF受体观察到的非冗余信号传导不能简单地通过两种TNF受体在各种细胞类型中的差异表达来解释，因为LM细胞在其表面表达的TNF-R2水平高于TNF-R1，并且LM细胞、NIH 3T3细胞和胸腺细胞均表达对应于两种受体类型的mRNA。因此，这两种受体可能启动不同的信号通路，导致诱导不同的细胞反应。
