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首页> 外文期刊>Infection and immunity >Interleukin-12 synthesis is a required step in trehalose dimycolate-induced activation of mouse peritoneal macrophages.
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Interleukin-12 synthesis is a required step in trehalose dimycolate-induced activation of mouse peritoneal macrophages.

机译：白介素12合成是海藻糖二甲藻酸酯诱导的小鼠腹膜巨噬细胞活化的必需步骤。

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Trehalose dimycolate (TDM), a glycolipid present in the cell wall of Mycobacterium spp., is a powerful immunostimulant. TDM primes murine macrophages (Mphi) to produce nitric oxide (NO) and to develop antitumoral activity upon activation with low doses of lipopolysaccharide (LPS). In this study, we investigated the ability of TDM to induce interleukin 12 (IL-12) and the role of this cytokine in TDM-induced activation of murine Mphi. RNA isolated from peritoneal exudate cells (PEC) collected at different times after TDM injection was used to determine IL-12 (p35 and p40 subunits) and gamma interferon (IFN-gamma) mRNA levels by semiquantitative reverse transcriptase-PCR. Constitutive expression of IL-12p35 was observed in PEC from untreated as well as from TDM-injected mice. In contrast, expression of the IL-12p40 subunit was almost undetectable in control PEC but was dramatically upregulated in PEC from TDM-injected mice. IL-12p40 expression peaked at 8 h and subsided to baseline levels at 39 h postinjection. TDM was also able to induce IFN-gamma expression; however, kinetics of induction of IFN-gamma was different from that of IL-12p40. Maximal levels of IFN-gamma mRNA were reached by 24 h and did not return to baseline by 4 days. In addition, pretreatment of mice with neutralizing monoclonal antibodies directed against IL-12 (C15.6.7 and C15.1.2) blocked IFN-gamma mRNA induction in PEC from TDM-treated mice. We further determined if the induction of IL-12 and/or IFN-gamma contributes to the in vivo priming effect of TDM on peritoneal Mphi. TDM-injected mice were treated in vivo with anti-IL-12 or anti-IFN-gamma (XMG.1.6) monoclonal antibodies. TDM-primed Mphi were then activated in vitro with LPS and tested for their ability to produce NO and to develop cytostatic activity toward cocultivated L1210 tumor cells. Priming of Mphi by TDM was completely blocked by in vivo neutralization of either IL-12 or IFN-gamma as demonstrated by an absence of tumoricidal activity and NO production by TDM-elicited Mphi in the presence of LPS. Taken together our results show that TDM, a defined molecule from M. tuberculosis, induces in vivo production of IL-12. Moreover, synthesis of IL-12 mediates TDM priming of mouse peritoneal Mphi through IFN-gamma induction.
机译：海藻糖二甲藻酸酯（TDM）是分枝杆菌属细胞壁中存在的糖脂，是一种强大的免疫刺激剂。 TDM引发鼠巨噬细胞（Mphi）以产生一氧化氮（NO），并在用低剂量脂多糖（LPS）激活后产生抗肿瘤活性。在这项研究中，我们调查了TDM诱导白介素12（IL-12）的能力以及该细胞因子在TDM诱导的鼠Mphi激活中的作用。在TDM注射后的不同时间从腹膜渗出细胞（PEC）分离的RNA用于通过半定量逆转录酶PCR测定IL-12（p35和p40亚基）和γ干扰素（IFN-γ）mRNA水平。在未治疗的和注射TDM的小鼠的PEC中观察到IL-12p35的组成型表达。相反，在对照PEC中几乎检测不到IL-12p40亚基的表达，但在注射TDM的小鼠的PEC中IL-12p40亚基的表达显着上调。 IL-12p40表达在注射后8小时达到峰值，并在注射后39小时降至基线水平。 TDM还能够诱导IFN-γ表达。然而，IFN-γ的诱导动力学不同于IL-12p40。 IFN-γmRNA的最大水平在24 h之前达到，并且在4天之前未恢复到基线。此外，用针对IL-12（C15.6.7和C15.1.2）的中和性单克隆抗体对小鼠进行预处理可阻止TDM处理的小鼠在PEC中诱导IFN-γmRNA。我们进一步确定IL-12和/或IFN-γ的诱导是否有助于TDM对腹膜Mphi的体内启动作用。用抗IL-12或抗IFN-γ（XMG.1.6）单克隆抗体体内处理TDM注射的小鼠。然后，用LPS在体外激活TDM引发的Mphi，并测试它们产生NO的能力以及对共培养的L1210肿瘤细胞产生细胞抑制活性的能力。 TLP对Mphi的启动被IL-12或IFN-γ的体内中和作用完全阻断，如在LPS存在下，无肿瘤活性和TDM诱导的Mphi没有产生NO所证明。总之，我们的结果表明TDM是结核分枝杆菌的一种确定分子，可诱导体内IL-12的产生。此外，IL-12的合成通过干扰素-γ介导介导小鼠腹膜Mphi的TDM启动。

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