Alleva D G, Askew D, Burger C J, Elgert K D
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406.
J Leukoc Biol. 1993 Aug;54(2):152-60. doi: 10.1002/jlb.54.2.152.
Tumors down-regulate T cell responses partly by increasing macrophage (m phi) production of the suppressive molecule prostaglandin E2 (PGE2). Because tumor growth increases m phi tumor necrosis factor alpha (TNF-alpha) production and TNF-alpha stimulates m phi PGE2 synthesis, we examined the contribution of TNF-alpha to fibrosarcoma-induced m phi-mediated suppression of alloreactive CD4+ T cell proliferation. We showed that tumor-bearing host (TBH) m phi s express high levels of TNF-alpha mRNA, which leads to increased lipopolysaccharide-induced TNF-alpha production. Tumor cells were directly involved in m phi TNF-alpha synthesis because fibrosarcoma cells induced normal host (NH) m phi s to produce TNF-alpha. Addition of TBH m phi s to allogeneic mixed lymphocyte reaction (MLR) cultures suppressed CD4+ T cell proliferation more than NH m phi s. The neutralization of endogenous TNF-alpha activity with anti-TNF-alpha antibody (Ab) treatment reversed TBH, but not NH, m phi-mediated suppression. Conversely, exogenous TNF-alpha increased NH or TBH m phi-mediated suppression but stimulated T cell proliferation without m phi s. Kinetic treatment of MLR cultures with anti-TNF-alpha Ab or TNF-alpha showed that TNF-alpha production and activity occurred at the beginning of T cell proliferation. When arachidonic acid metabolite synthesis was inhibited, TNF-alpha-induced suppression was blocked in NH m phi-containing cultures and completely reversed in TBH m phi-containing cultures. A PGE2-specific enzyme-linked immunosorbent assay showed that TNF-alpha addition increased PGE2 production in NH m phi-containing cultures to that of TBH m phi-containing cultures. Exogenous PGE2 did not affect the TNF-alpha enhancement of T cell proliferation without m phi s. Therefore, suppression induced by TNF-alpha was caused by increased m phi PGE2 production and not by TNF-alpha in concert with PGE2. Even though TNF-alpha is known to enhance lymphocyte proliferation, we show that in the presence of m phi s, the main TNF-alpha producers, TNF-alpha suppresses T cell proliferation. Perhaps increased TNF-alpha production during pathological states, such as cancer, triggers the initial stages of suppression.
肿瘤部分通过增加巨噬细胞（m phi）产生抑制性分子前列腺素E2（PGE2）来下调T细胞反应。由于肿瘤生长会增加m phi肿瘤坏死因子α（TNF-α）的产生，且TNF-α会刺激m phi合成PGE2，因此我们研究了TNF-α在纤维肉瘤诱导的m phi介导的同种异体反应性CD4 + T细胞增殖抑制中的作用。我们发现荷瘤宿主（TBH）的m phi表达高水平的TNF-α mRNA，这导致脂多糖诱导的TNF-α产生增加。肿瘤细胞直接参与m phi的TNF-α合成，因为纤维肉瘤细胞可诱导正常宿主（NH）的m phi产生TNF-α。将TBH的m phi添加到同种异体混合淋巴细胞反应（MLR）培养物中比NH的m phi更能抑制CD4 + T细胞增殖。用抗TNF-α抗体（Ab）处理中和内源性TNF-α活性可逆转TBH而非NH的m phi介导的抑制作用。相反，外源性TNF-α增加了NH或TBH的m phi介导的抑制作用，但在没有m phi的情况下刺激了T细胞增殖。用抗TNF-α Ab或TNF-α对MLR培养物进行动力学处理表明，TNF-α的产生和活性发生在T细胞增殖开始时。当花生四烯酸代谢产物合成受到抑制时，TNF-α诱导的抑制作用在含NH m phi的培养物中被阻断，而在含TBH m phi的培养物中完全逆转。一项PGE2特异性酶联免疫吸附试验表明，添加TNF-α可使含NH m phi的培养物中的PGE2产生增加至含TBH m phi的培养物中的水平。外源性PGE2在没有m phi的情况下不影响TNF-α对T细胞增殖的增强作用。因此，TNF-α诱导的抑制作用是由m phi的PGE2产生增加引起的，而不是由TNF-α与PGE2协同作用引起的。尽管已知TNF-α可增强淋巴细胞增殖，但我们发现，在主要TNF-α产生者m phi存在的情况下，TNF-α会抑制T细胞增殖。也许在诸如癌症等病理状态下TNF-α产生的增加触发了抑制的初始阶段。
