Regulatory mechanisms underlying IL-12 production and the control of immune responses

IL-12 产生和免疫反应控制的调控机制

• 批准号: 08839013
• 负责人: ONO Shiro
• 金额: $ 1.41万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08839013/
• 关键词: macrophages; IL-12; IL-10; PGE2; adjuvant; STK; CD40; autoimmune disease; 自己免疫; サイトカイン; マイクロファージ; 遺伝子支配; Th1

IL-12 secreted by macrophages (Mphi) is a critical cytokine for the induction of Th1 cells responsible for cellular immunity. Here we investigated mechanisms underlying the regulation of IL-12 production. 1. The non-MHC linked strain difference in the T-cell independent IL-12 production by murine splenic Mphi to LPS plus IFN-gamma stimulation was closely related with simultaneous production of IL-10 capable of inhibiting IL-12 synthesis. 2. In contrast to splenic Mphi, peritoneal Mphi failed to induce IL-12 upon stimulation with LPS + IFN-gamma or SAC + IFN-gamma due to high production of IL-10 and PGE2.3. Peritoneal Mphi from mice given complete Freund's adjuvant (CFA) acquired the ability to produce IL-12 to the stimulation. Interestingly, levels of IL-10 and PGE2 were markedly reduced in such CFA-treated peritoneal Mphi. 4. Analyzes of cell surface antigens by flow cytometry revealed that the expression of STK (stem cell-derived tyrosine kinase, a member of the hepatocyte growth factor receptor family) on normal peritoneal Mphi was remarkably decreased after CFA-treatment. This implies the association of IL-12-producing ability with downregulation of STK as well as IL-10 and PGE2.5. High IL-12 production was induced even by untreated peritoneal Mphi from SJL/J mice exhibing a high incidence of experimental autoimmune encephalomyelitis mediated by Th1 cells and from MRL/Ipr mice spontaneously developing systemic autoimmune disease. 6. The presence of B cells constitutively expressing CD40 dramatically inhibited the T-cell dependent IL-12 induction to Con A or anti-CD3epsilon mAb stimulation, in which T-Mphi cell interaction through CD40L-CD40 molecules was required. This inhibition seemed to be caused by a competitive blocking of T-Mphi cell interaction by B cells incapable of producing IL-12.

巨噬细胞（Mphi）分泌的IL-12是诱导Th1细胞参与细胞免疫的关键细胞因子。在这里，我们研究了调控IL-12产生的机制。1. 小鼠脾Mphi在LPS + ifn - γ刺激下t细胞独立IL-12产生的非mhc相关品系差异与同时产生能够抑制IL-12合成的IL-10密切相关。2. 与脾Mphi相比，腹腔Mphi在LPS + ifn - γ或SAC + ifn - γ刺激下，由于IL-10和PGE2.3的高产量，无法诱导IL-12。给予完全弗氏佐剂（CFA）的小鼠腹膜Mphi在刺激下获得了产生IL-12的能力。有趣的是，在cfa处理的腹膜Mphi中，IL-10和PGE2水平显著降低。流式细胞术分析细胞表面抗原发现，cfa治疗后，STK（干细胞来源的酪氨酸激酶，肝细胞生长因子受体家族成员）在正常腹膜Mphi上的表达显著降低。这表明il -12的产生能力与STK、IL-10和PGE2.5的下调有关。即使未经处理的腹膜Mphi也能诱导高IL-12的产生，SJL/J小鼠表现出Th1细胞介导的实验性自身免疫性脑脊髓炎的高发，MRL/Ipr小鼠自发发生全身性自身免疫性疾病。6. 组成性表达CD40的B细胞显著抑制t细胞依赖性IL-12诱导Con A或抗cd3epsilon mAb刺激，其中T-Mphi细胞通过CD40L-CD40分子相互作用是必需的。这种抑制似乎是由无法产生IL-12的B细胞竞争性阻断T-Mphi细胞相互作用引起的。

项目成果

Takenaka, H.et al.: "Regulation of T cell-dependent and -independent IL-12 production by the three Th2-type cytokines IL-10, IL-6, and IL-4." J.Leukoc.Biol.61. 80-87 (1997)

Takenaka, H.等人：“三种 Th2 型细胞因子 IL-10、IL-6 和 IL-4 对 T 细胞依赖性和非依赖性 IL-12 产生的调节。”

Maruo,S.et al.: "B cells regulate CD40 ligand-induced IL-12 production in antigen-presenting cells(APC)during T cell-APC interactions." J.Immunol.158. 120-126 (1997)

Maruo,S.et al.：“在 T 细胞-APC 相互作用期间，B 细胞调节抗原呈递细胞 (APC) 中 CD40 配体诱导的 IL-12 产生。”

Maruo,S.: "B cell regulate CD40 ligand-induced IL-12 production in antigen-presenting cells(APC) during T cell/APC interactions." J.Immunol.158. 120-126 (1997)

Maruo,S.：“在 T 细胞/APC 相互作用期间，B 细胞调节抗原呈递细胞 (APC) 中 CD40 配体诱导的 IL-12 产生。”

S.Maruo et al.: "IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T helper cell clones." J.Immunol.156. 1748-1755 (1996)

S.Maruo 等人：“抗原呈递细胞产生的 IL-12 诱导 T 辅助细胞克隆的不依赖于 IL-2 的增殖。”

X.-G.Tai et al.: "A role for CD9 molecules in T cell activation." J.Exp.Mrd.184. 753-758 (1996)

X.-G.Tai 等人：“CD9 分子在 T 细胞激活中的作用。”