INTERLEUKIN-12 AND TUMOR-NECROSIS-FACTOR-ALPHA ARE COSTIMULATORS OF INTERFERON-GAMMA PRODUCTION BY NATURAL-KILLER-CELLS IN SEVERE COMBINED IMMUNODEFICIENCY MICE WITH LISTERIOSIS, AND INTERLEUKIN-10 IS A PHYSIOLOGICAL ANTAGONIST
INTERLEUKIN-12 AND TUMOR-NECROSIS-FACTOR-ALPHA ARE COSTIMULATORS OF INTERFERON-GAMMA PRODUCTION BY NATURAL-KILLER-CELLS IN SEVERE COMBINED IMMUNODEFICIENCY MICE WITH LISTERIOSIS, AND INTERLEUKIN-10 IS A PHYSIOLOGICAL ANTAGONIST
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DOI：
10.1073/pnas.90.8.3725
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发表时间：
1993-04-15
影响因子：
11.1
通讯作者：
UNANUE, ER
中科院分区：
文献类型：
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作者：
TRIPP, CS;WOLF, SF;UNANUE, ER
具有严重联合免疫缺陷（SCID）突变的小鼠中的李斯特菌病是在自然免疫发展期间由自然杀伤（NK）细胞激活的干扰素γ（IFN-γ）依赖性巨噬细胞的体内和体外模型。我们证明，从SCID脾细胞产生IFN-γ刺激白细胞介素（IL）12，肿瘤坏死因子α（TNF-α），IL-2，但抑制IL-10。IL-10、IL-12和TNF由来自SCID脾细胞和腹膜巨噬细胞的热灭活单核细胞增生李斯特菌（hk-LM）诱导。IL-12的产生是hk-LM刺激SCID脾细胞产生IFN-γ所必需的，因为IL-12的中和完全阻断了该系统中IFN-γ的产生。TNF-α和IL-2与IL-12协同作用以增加IFN-γ的产生。此外，外源性IL-2增加NK细胞对hk-LM或IL-12和TNF-α的应答。相比之下，IL-10在两个水平上抑制hk-LM诱导的IFN-γ产生：（i）通过抑制这些培养物（推测来自巨噬细胞）的TNF和IL-12产生和（ii）通过抑制IL-12和TNF-α对NK细胞IFN-γ产生的刺激作用。因此，这些数据表明，TNF-α和IL-12的巨噬细胞产生刺激NK细胞释放IFN-γ，并且响应于hk-LM产生的IL-10在巨噬细胞和NK细胞水平抑制这种应答。
Listeriosis in mice with the severe combined immunodeficiency (SCID) mutation is an established model in vivo and in vitro of interferon gamma (IFN-gamma)-dependent macrophage activation by natural killer (NK) cells during the development of natural immunity. We demonstrate that IFN-gamma production from SCID splenocytes is stimulated by interleukin (IL) 12, tumor necrosis factor alpha (TNF-alpha), and IL-2 but is inhibited by IL-10. IL-10, IL-12, and TNF are induced by heat-killed Listeria monocytogenes (hk-LM) from SCID splenocytes and peritoneal macrophages. IL-12 production is necessary for hk-LM to stimulate IFN-gamma production by SCID splenocytes since neutralization of IL-12 totally blocks IFN-gamma production in this system. TNF-alpha and IL-2 act synergistically with IL-12 to augment IFN-gamma production. Also, exogenous IL-2 increases the response of NK cells to hk-LM or to IL-12 and TNF-alpha. In contrast, IL-10 inhibits hk-LM-induced IFN-gamma production at two levels: (i) by inhibiting TNF and IL-12 production from these cultures (presumably from the macrophage) and (ii) by inhibiting the stimulatory effects of IL-12 and TNF-alpha on NK-cell IFN-gamma production. Thus, these data indicate that macrophage production of TNF-alpha and IL-12 stimulates the release of IFN-gamma by NK cells and that IL-10 produced in response to hk-LM inhibits this response at the level of the macrophage and the NK cell.