The initiation and amplification of an inflammatory response depend on the action of transcription factors which induce the genes for adhesion and chemotactic molecules and cytokines. A growing number of transcription factor families, including NF-kappaB, C/EBP, and AP-1 are known to be vital targets of signal transduction pathways that lead to proinflammatory gene activation. In the current funding period, we isolated and characterized a transcription factor, ATF-2 (mXBP) which bound to a CRE- element in the MHC class II A-alpha promoter. By targeted gene disruption, we then produced mice lacking ATF-2. Studies of ATF-2-deficient mice now reveal that this member of the ATF/CREB family of transcription factors is also an important proinflammatory molecule. ATF-2 has widespread effects on induction of immediate early genes, adhesion molecules, chemokines, and cytokines, with potentially important effects on the inflammatory response found in joints and internal organs in infectious and rheumatic diseases. In this renewal application we propose to perform in vitro studies to delineate the molecular mechanism for ATF2's proinflammatory effect. These studies use molecular approaches to establish the role of ATF-2 in each step of the cascade of cytokine induction. We will also directly test the role of ATF-2 in the in vivo inflammatory response. Three models of inflammation will be studied: endotoxin-D-gal-septic shock, carditis induced by the Lyme agent, B. burgdorferi and Coxsackievirus B myocarditis. Finally, we will assess the role of ATF-2 in three rheumatic syndromes: HTLV-1-related synovitis and Sjogren's syndrome, and TNF-alpha induced polyarthritis. This work will identify potential targets for the blockade of ATF-2 action, and could lead to new therapies for inflammatory diseases.
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