ENDOGENOUS MECHANISMS THAT LIMIT INFLAMMATION

描述：(改编自《调查者摘要》)：巨噬细胞起着关键作用 部分通过产生炎症来调节炎症的作用 细胞因子。响应于干扰素-g的启动和二次激活信号， 巨噬细胞产生高水平的IL-12，进而诱导产生干扰素-g 并促进TH1型免疫应答的产生。重要的是，炎症性 应对措施通常是自我限制的，当放松管制时，可能会导致 过度的组织损伤。虽然监管机制涉及限制 炎症反应在很大程度上仍然是未知的，我们发现暴露前 对肿瘤坏死因子-a或清道夫受体配体有明显抑制作用 巨噬细胞分泌IL-12。抑制IL-12不需要产生 已确定的巨噬细胞激活抑制物包括IL-10、IL-4或PGE2。这个 拟议研究的目标是定义细胞和分子 介导这些新的内源性调节效应的机制--肿瘤坏死因子-a和 清道夫受体配体。 在目标1中，我们将测试假设肿瘤坏死因子-a和清道夫受体配体是 体内和体外重要的内源性炎症调节因子 确定刺激暴露的顺序，这在调节中是关键的 IL-12的表达，该机制是否抑制额外的炎症 细胞因子的表达，以及额外的激活信号(包括 CD4OL、内毒素和透明质酸)，抑制IL-12。在目标2和目标3中，我们将检验假设 肿瘤坏死因子-α(2)和清道夫受体配体(3)抑制血管内皮细胞活化 炎症基因表达和鉴定所需的转录因子 所涉及的监管机制针对的顺式作用元件。我们会 也要检验环戊烯酮前列腺素在 肿瘤坏死因子-α和清道夫受体介导的细胞因子产生抑制和IF 因此，无论它们是通过依赖于PPARy的途径还是不依赖于PPARy的途径发挥作用 涉及对IK激酶的抑制和对核因子-KB的抑制。在《目标3》中，我们将 验证肿瘤坏死因子-a和清道夫抗炎作用的假设 体内观察到的受体至少部分是由于它们抑制的能力 产生促炎细胞因子。

DESCRIPTION: (Adapted from the Investigator's abstract): Macrophages play a key role in regulating inflammation in part through the production of inflammatory cytokines. In response to priming by IFN-g and a secondary activation signal, macrophages produce high levels of IL-12 that in turn induces IFN-g production and promotes generation of TH1 type immune response. Importantly, inflammatory responses are typically self-limiting and when deregulated, can lead to excessive tissue damage. While the regulatory mechanisms involved limiting the inflammatory response remain largely undefined, we discovered that pre-exposure to TNF-a or scavenger receptor ligands markedly inhibited the production of IL-12 by macrophages. Inhibition of IL- 12 did not require the production of defined inhibitors of macrophage activation including, IL-10, IL-4 or PGE2. The objective of the proposed studies is to define the cellular and molecular mechanisms that mediate these novel endogenous regulatory effects of TNF-a and scavenger receptor ligands. In Aim 1 we will test the hypothesis TNF-a and scavenger receptor ligands are important endogenous regulators of inflammation both in vitro and in vivo by determining the sequence of exposure to stimuli that is critical in regulating IL-12 expression, whether this mechanism inhibits additional inflammatory cytokine expression, and whether additional activational signals (including CD4OL, LPS and HA), inhibit IL-12. In Aims 2 and 3 we will test the hypotheses that TNF-a (2) and scavenger receptor ligands (3) inhibit the activation of transcription factors required for inflammatory gene expression and identify the cis-acting elements targeted by the regulatory mechanisms involved. We will also test the hypothesis that cyclopentenone prostaglandins play a role in TNF-a- and scavenger receptor-mediated inhibition of cytokine production and if so whether they act through a PPARy-dependent, or a PPARy-independent pathway involving the inhibition of IK kinase and inhibition of NF-KB. In Aim 3 we will test the hypothesis that the anti-inflammatory effects of TNF-a and scavenger receptor observed in vivo are due at least in part to their capacity to inhibit production of pro-inflammatory cytokines.