The effectiveness of non-specific and cyclooxygenase (COX)-2-specific non-steroidal anti-inflammatory drugs for treatment of the pain, swelling, and stiffness of arthritis provides clinical evidence that increased prostaglandin (PG) production is an important contributor to the disease process. PG biosynthesis requires the sequential action of COX-1 or COX-2 and terminal synthases to generate PGs that function as pleiotropic mediators by acting on a variety of cell surface receptors. After stimulation with pro-inflammatory cytokines, there is a preferential increase of PGE2 in many different cell types and tissues including the synovium. We demonstrated that increased PGE2 in these tissues requires the inducible PGE synthase, microsomal PGE synthase (mPGES)-1. We have also shown that absence of mPGES-1 results in a shift of the PG profile of cells and tissues, with the specific profile dependent on the other synthases present. For this reason, absence or inhibition of mPGES-1 is a markedly different biology than absence or inhibition of COX. The overall goal of this proposal is to characterize the role of mPGES-1 in immune inflammatory arthritis and how it differs from the role of COX-2. We hypothesize that upregulated mPGES-1 is required for the production of PGE2 and that its specific absence or inhibition results in an altered eicosanoid profile that fundamentally changes the immune inflammatory response. To evaluate this hypothesis, we will make use of mice genetically deficient in mPGES-1 (Dba1/LacJ.mPGES-1 -/-) and inhibition of mPGES-1 using a specific inhibitor with activity in humans and mice (AF3485). We will determine the role for mPGES-1-derived PGE2 in comparison with other eicosanoids for initiation and progression of inflammation and immunity. We will determine the specific role of mPGES-1 deficiency for the developing immune response. Having shown profound differences in T- dependent humoral immune responses and in the Th phenotype, we will determine the mechanism by which mPGES-1 deficiency leads to these changes. In order to translate these findings, we will evaluate the differences between COX inhibition and mPGES-1 inhibition in human immune and inflammatory responses. We will determine effects of different compounds that inhibit PG production on T-helper phenotype and induced T-regulatory cells. These data will provide the scientific basis by which to determine if mPGES-1 is an appropriate target for therapeutic intervention in arthritis.
The discovery of COX-2 and subsequent development of specific COX-2 inhibitors represented an enormous conceptual advance in eicosanoid biology and opened new possibilities for pharmacologic treatment of inflammation and pain. It is clear, however, that COX-2-specific NSAIDs have their own toxicities. The finding of a PGE synthase isoform induced during inflammation and required for high level PGE2 production represents a conceptual advance of similar magnitude. In view of the existence of multiple PGES enzymes and other PG subclasses, the specific role of mPGES-1-derived PGE2 in inflammation and autoimmunity remains uncertain. Furthermore, information on the biology that will inform the development of mPGES-1 as a therapeutic target remains incomplete. It is our expectation that our work will yield new insights into the role of PGs in the functioning of eicosanoids during initiation and resolution of inflammation and the transition from the innate to the acquired immune response.
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