Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells.
Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells.
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DOI：
10.1084/jem.178.3.1041
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发表时间：
1993-09-01
影响因子：
15.3
通讯作者：
Trinchieri, G
中科院分区：
文献类型：
--
作者：
D'Andrea, A;Aste-Amezaga, M;Valiante, N M;Ma, X;Kubin, M;Trinchieri, G
自然杀伤细胞刺激因子或白细胞介素12（NKSF/IL-12）是由单核细胞/巨噬细胞、B细胞和可能的其他辅助细胞类型主要响应于细菌或细菌产物而产生的异源二聚体细胞因子。NKSF/IL-12介导对T和NK细胞的多形生物学活性，并且单独或与其他诱导剂协同，是干扰素γ（IFN-γ）产生的强大刺激剂。IL-10是单核细胞-巨噬细胞活化的有效抑制剂，其抑制肿瘤坏死因子α（TNF-α）、IL-1以及IFN-γ从在辅助细胞水平起作用的淋巴细胞的产生。由于TNF-α和IL-1不是IFN-γ的有效诱导剂，IL-10抑制IFN-γ产生的机制尚不清楚。在本文中，我们表明，IL-10是一个有效的抑制剂NKSF/IL-12的生产从人外周血单核细胞激活金黄色葡萄球菌或脂多糖（LPS）。游离NKSF/IL-12 p40链和生物活性p70异二聚体的产生均被IL- 10阻断。S.金黄色葡萄球菌或LPS可下调p35 mRNA的表达，而p35 mRNA的表达可被S.金黄色葡萄球菌、LPS或IL-10。尽管IL-10能够阻断NKSF/IL-12（一种在体外和体内的IFN-γ的强诱导剂）的产生，但是IL-10抑制IFN-γ的机制不能仅基于抑制NKSF/IL-12来解释，因为IL-10可以部分抑制由NKSF/IL-12诱导的IFN-γ产生，并且，在存在针对NKSF/IL-12的中和抗体的情况下，响应于各种刺激的IFN-γ产生。我们的发现是，针对NKSF/IL-12、TNF-α或IL-1 β的抗体可以显著抑制响应于各种刺激的IFN-γ产生，并且NKSF/IL-12和IL-1 β可以克服IL-10介导的IFN-γ抑制，这表明IL-10对IFN-γ产生的抑制主要是由于其阻断IFN-γ诱导剂NKSF/IL-12的辅助细胞的产生，以及共刺激分子IL-1 β。
Natural killer cell stimulatory factor or interleukin 12 (NKSF/IL-12) is a heterodimeric cytokine produced by monocytes/macrophages, B cells, and possibly other accessory cell types primarily in response to bacteria or bacterial products. NKSF/IL-12 mediates pleiomorphic biological activity on T and NK cells and, alone or in synergy with other inducers, is a powerful stimulator of interferon gamma (IFN- gamma) production. IL-10 is a potent inhibitor of monocyte-macrophage activation, that inhibits production of tumor necrosis factor alpha (TNF-alpha), IL-1 and also IFN-gamma from lymphocytes acting at the level of accessory cells. Because TNF-alpha and IL-1 are not efficient inducers of IFN-gamma, the mechanism by which IL-10 inhibits IFN-gamma production is not clear. In this paper, we show that IL-10 is a potent inhibitor of NKSF/IL-12 production from human peripheral blood mononuclear cells activated with Staphylococcus aureus or lipopolysaccharide (LPS). Both the production of the free NKSF/IL-12 p40 chain and the biologically active p70 heterodimer are blocked by IL- 10. NKSF/IL-12 p40 chain mRNA accumulation is strongly induced by S. aureus or LPS and downregulated by IL-10, whereas the p35 mRNA is constitutively expressed and only minimally regulated by S. aureus, LPS, or IL-10. Although IL-10 is able to block the production of NKSF/IL-12, a powerful inducer of IFN-gamma both in vitro and in vivo, the mechanism of inhibition of IFN-gamma by IL-10 cannot be explained only on the basis of inhibition of NKSF/IL-12 because IL-10 can partially inhibit IFN-gamma production induced by NKSF/IL-12, and also, the IFN-gamma production in response to various stimuli in the presence of neutralizing antibodies to NKSF/IL-12. Our findings that antibodies against NKSF/IL-12, TNF-alpha, or IL-1 beta can significantly inhibit IFN-gamma production in response to various stimuli and that NKSF/IL-12 and IL-1 beta can overcome the IL-10-mediated inhibition of IFN-gamma, suggest that IL-10 inhibition of IFN-gamma production is primarily due to its blocking production from accessory cells of the IFN-gamma- inducer NKSF/IL-12, as well as the costimulating molecule IL-1 beta.