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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049010-11
Application #
8598456
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
2002-07-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
11
Fiscal Year
2014
Total Cost
$274,687
Indirect Cost
$99,727
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Maseda, Damian; Johnson, Elizabeth M; Nyhoff, Lindsay E et al. (2018) mPGES1-Dependent Prostaglandin E2 (PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2 Production. J Immunol 200:725-736
Nyhoff, Lindsay E; Crofford, Leslie J; Kendall, Peggy L (2017) Reply. Arthritis Rheumatol 69:475-477
Nyhoff, Lindsay E; Barron, Bridgette L; Johnson, Elizabeth M et al. (2016) Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex-Mediated Inflammatory Arthritis. Arthritis Rheumatol 68:1856-68
Crofford, Leslie J; Nyhoff, Lindsay E; Sheehan, Jonathan H et al. (2016) The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy. Expert Rev Clin Immunol 12:763-73
Maseda, Damian; Bonami, Rachel H; Crofford, Leslie J (2014) Regulation of B lymphocytes and plasma cells by innate immune mechanisms and stromal cells in rheumatoid arthritis. Expert Rev Clin Immunol 10:747-62
Frolov, Andrey; Dong, Hua; Jiang, Min et al. (2013) Niemann-pick type C2 deficiency in human fibroblasts confers robust and selective activation of prostaglandin E2 biosynthesis. J Biol Chem 288:23696-703
McCarthy, Mary K; Levine, Rachael E; Procario, Megan C et al. (2013) Prostaglandin E2 induction during mouse adenovirus type 1 respiratory infection regulates inflammatory mediator generation but does not affect viral pathogenesis. PLoS One 8:e77628
Frolov, Andrey; Yang, Lihua; Dong, Hua et al. (2013) Anti-inflammatory properties of prostaglandin E2: deletion of microsomal prostaglandin E synthase-1 exacerbates non-immune inflammatory arthritis in mice. Prostaglandins Leukot Essent Fatty Acids 89:351-8
Mason, Katie L; Rogers, Lisa M; Soares, Elyara M et al. (2013) Intrauterine group A streptococcal infections are exacerbated by prostaglandin E2. J Immunol 191:2457-65
Kojima, Fumiaki; Frolov, Andrey; Matnani, Rahul et al. (2013) Reduced T cell-dependent humoral immune response in microsomal prostaglandin E synthase-1 null mice is mediated by nonhematopoietic cells. J Immunol 191:4979-88

Showing the most recent 10 out of 20 publications