):Lipopolysaccharide (LPS; also known as endotoxin), derived from the outer membrane of gram negative bacteria, is one of the principal activators of the sepsis cascade. Although we have known of endotoxin's powerful effects on the immune system for over 100 years, a clear understanding of how this bacterial constituent can elicit host responses is still lacking. A better understanding of the molecular mechanisms through which endotoxin regulates inflammatory and anti-inflammatory gene expression will provide new targets for the development of therapies aimed at controlling the cascade of events induced during a gram negative bacterial infection. It is the long-term goal of this research to provide information on these new targets by characterizing both the nuclear and cytoplasmic signaling mechanisms through which LPS acts to induce inflammatory and anti-inflammatory gene expression in monocytes and macrophages. The proposed studies seek to define the nuclear events, elicited by LPS, which lead to the expression of the anti-inflammatory secretory IL-1Ra (sIL-1Ra) gene in macrophages. At least four distinct LPS response elements (LREs) are involved in inducing sIL-1Ra gene expression in response to LPS. Our previous studies have identified the transcription factors which bind to two of these (LRE1 and 3) as the myeloid-specific factor PU.1.
Specific Aim 1 will characterize the mechanisms through which the PU.1 transcription factor regulates LPS-inducible gene expression in macrophages.
Specific Aim 2 will characterize a newly-discovered major LPS responsive promoter element located between B3.4 and B1.7 kb upstream of the transcription start site of the sIL-1Ra gene and develop a transgenic mouse model in order to study the role of the distal enhancer element in the regulation of gene expression in vivo.
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| Gautam, Jitendra K; Ashish; Comeau, Laurey D et al. (2006) Structural and functional evidence for the role of the TLR2 DD loop in TLR1/TLR2 heterodimerization and signaling. J Biol Chem 281:30132-42 |
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