Abstract

The effectiveness of non-steroidal anti-inflammatory drugs and specific cyclooxygenase (COX)-2 inhibitors for treatment of arthritis provides clinical evidence that increased prostaglandin (PG) production in joint tissues contributes to symptoms of pain, swelling, and stiffness. PG biosynthesis requires the sequential action of COX and PG synthase enzymes. After stimulation with pro-inflammatory cytokines, there is a preferential increase in PGE2 in many different cell types, including synovial fibroblasts. We demonstrated that increased PGE2 in response to pro-inflammatory cytokines in human primary synovial cells is due to induction of microsomal PGE synthase (mPGES)-1. The overall goal of this proposal is to characterize the role of mPGES-1 and other PGE synthases in eicosanoid biosynthesis in immune inflammatory arthritis. We hypothesize a requirement for mPGES-1 to achieve maximal PGE2 production and a role for mPGES-1-derived PGE2 in shaping the immune inflammatory response. We propose to determine the specific role of mPGES-1 relative to other synthetic enzymes for biosynthesis of PGE2 in human synovial fibroblasts using specific COX enzyme inhibitors and inhibitory RNA (RNAi). We will investigate eicosanoid production pathways in cells from mice deficient for COX-1, COX-2 or mPGES-1. Expression of the COX and PGES enzymes in synovial tissues from patients with arthritis or non-arthritic subjects and their relative subcellular localization will be determined. In addition, we will examine the consequences of mPGES-1 deficiency for innate and acquired immunity in genetically null mice. We will determine eicosanoid and cytokine profiles of macrophages, splenocytes, and dendritic cells in mPGES-1 null mice. We will determine the impact of mPGES-1 deficiency on dendritic cell phenotype and function. We will determine the role of PGE2 on immune versus inflammatory mechanisms of arthritis using the collagen-induced arthritis and K/BxN serum models. These data will provide the scientific basis by which to determine if mPGES-1 is an appropriate target for therapeutic intervention in arthritis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049010-04
Application #
7169268
Study Section
Special Emphasis Panel (ZRG1-ACTS (01))
Program Officer
Mancini, Marie
Project Start
2004-12-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
4
Fiscal Year
2007
Total Cost
$316,018
Indirect Cost

  Institution

Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506

  Publications

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

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