The objective of this proposal is to determine how TTP and TIA-1 modify the initiation and resolution of? inflammatory arthritis. TTP and TIA-1 are RNA-binding proteins that regulate the stability and translation? of selected mRNAs that encode pro-inflammatory proteins involved in the pathogenesis of arthritis.? Mutant mice lacking TTP and TIA-1 overexress pro-inflammatory proteins and develop spontaneous? arthritis. These mice also overproduce bone marrow and peripheral blood neutrophils that aberrantly? overexpress TNF. TTP and TIA-1 also modulate arthritis induced by anti-glucose-6-phosphate isomerase? (GPI) antibodies. In response to anti-GPI, TTP-/- mice develop arthritis more quickly than wild type? controls. Remarkably, the resolution phase of synovial inflammation is markedly accelerated in mice? lacking either TIA-1 or TTP. Thus, TTP and TIA-1 are disease modifiers that have profound effects on? both the initiation and resolution of synovial inflammation. We hypothesize that these effects result from? altered expression of proteins and/or lipid mediators that either promote or inhibit inflammation. We? further hypothesize that neutrophils, an important source of both pro- and anti-inflammatory compounds,? play a key role in bringing about the modulatory effects of TTP and TIA-1.
The specific aims of this? propsal are: 1) To determine the role of neutrophils in spontaneous and anti-GPI-induced arthritis in TIA-1-? /-TTP-/- mice, 2) To identify neutrophil-derived pro-inflammatory proteins required for synovial? inflammation, 3) To determine how TIA-1 and TTP regulate the expression of inflammatory effector? molecules in neutrophils, and 4) To determine how TIA-1 and TTP regulate the resolution phase of the? inflammatory response.
These aims will be accomplished by determining whether neutrophil depletion? and/or TNF blockade prevents arthritis in these animals. We will use adoptive transfer experiments to? identify neutrophil-derived inflammatory mediators required for synovial inflammation. Finally, we will? determine how TIA-1 and TTP regulate the resolution of synovial inflammation.
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