ENDOGENOUS MECHANISMS THAT LIMIT INFLAMMATION

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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.