Two new mechanisms of suppression of inflammatory responses, mediated by the Toll-like receptor, TLRS and the transcription factor, lRF-3, will be studied at the cellular and organismal levels. TLRS is a sensor of double-stranded RNA and has been studied in the context of immediate innate responses to virus infection. But TLRS can also mediate response to endogenous cellular dsRNAs generated during a vahety of tissue injuries. One ofthe major findings in the current funding period was that the phosphorylation of tyrosine residues in TLRS is essential for its ability to initiate signaling.
In specific aim 1, the regulation of Tyr phosphorylation of TLRS will be investigated with emphasis upon the role of the tyrosine-kinase activity of EGF receptors, which were found by us to interact with TLRS. A unique property of TLRS is its exclusive use of the adaptor protein TRIF for the activation of transcription factors IRFS and NFKB. Surprisingly, we have discovered a TRIF-independent activity of TLRS that requires the recruitment and activation of the proto?? oncogene Src and causes inhibition of cell migration. In the second specific aim, the requirements for and consequences of Src activation by TLRS will be defined and the cellular and physiologic consequences will be evaluated. Finally, we have recently observed that IRFS has a significant suppressive effect on the pro?? inflammatory transcription factor, NFKB. The third specific aim will identify the structural features of the two proteins that mediate their physical interaction, and determine the biochemical, cellular and physiologic consequences ofthis interaction. The proposed experiments will test the hypothesis that TLRS and its associated components are coupled with both stimulus (dsRNA) dependent and independent functions that collectively impact upon pro-inflammatory gene expression and trafficking of pro-inflammatory leukocytes. These functions are likely to operate in a cell type and tissue restricted fashion and have significant impact on inflammatory disease and the associated effect on tumorigenesis. Interactions with projects 2, S, 4 and core B will be essential to assess how these functions and their control will impact inflammation related tumongenesis.
Results from the proposed studies will shed light on the anti-inflammatory role of TLRS signaling by inhibiting inflammatory cell migration and that of IRF-S by inhibiting inflammatory gene induction by NFkB. They will also connect the actions of two oncoproteins, Src and EGF receptor, to TLRS signaling, thus revealing a new aspect of interplay between inflammation and cancer.
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