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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