ENDOGENOUS MECHANISMS THAT LIMIT INFLAMMATION

描述：（改编自研究者摘要）：宏观调控发挥关键作用 在调节炎症中的作用，部分是通过产生炎性 细胞因子响应于IFN-g和次级激活信号的引发， 巨噬细胞产生高水平的IL-12，进而诱导IFN-γ的产生 并促进TH 1型免疫应答的产生。重要的是，炎症 反应通常是自限性的，当放松管制时，可能导致 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不明确，我们发现暴露前 TNF-α或清道夫受体配体显著抑制了 巨噬细胞IL-12。IL- 12的抑制不需要产生 确定的巨噬细胞活化抑制剂，包括IL-10、IL-4或PGE 2。的 拟议研究的目的是确定细胞和分子 介导TNF-α和TNF-α的这些新的内源性调节作用的机制 清道夫受体配体。 在目的1中，我们将检验TNF-α和清道夫受体配体是 重要的内源性炎症调节因子在体外和体内， 确定暴露于刺激的顺序，这对调节 IL-12表达，这种机制是否抑制了额外的炎症反应， 细胞因子表达，以及是否有额外的激活信号（包括 CD 4 OL、LPS和HA），抑制IL-12。在目标2和3中，我们将检验假设 TNF-α（2）和清道夫受体配体（3）抑制了 炎症基因表达所需的转录因子和鉴定 所涉及的调控机制所针对的顺式作用元件。我们将 还测试了环戊烯酮类化合物在 TNF-α和清道夫受体介导的细胞因子产生的抑制， 所以不管它们是通过依赖还是非依赖的途径起作用 涉及IK激酶的抑制和NF-κ B的抑制。在目标3中， 检验TNF-α和清道夫的抗炎作用 在体内观察到的受体至少部分是由于它们抑制 促炎细胞因子的产生。

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.