Defective Generation of a Humoral Immune Response Is Associated with a Reduced Incidence and Severity of Collagen-Induced Arthritis in Microsomal Prostaglandin E Synthase-1 Null Mice

Abstract

Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase and specifically catalyzes the conversion of PGH2 to PGE2. The present study demonstrates the effect of genetic deletion of mPGES-1 on the developing immunologic responses and its impact on the clinical model of bovine collagen-induced arthritis. mPGES-1 null and heterozygous mice exhibited decreased incidence and severity of arthritis compared with wild-type mice in a gene dose-dependent manner. Histopathological examination revealed significant reduction in lining hyperplasia and tissue destruction in mPGES-1 null mice compared with their wild-type littermates. mPGES-1 deficient mice also exhibited attenuation of mechanical nociception in a gene dose-dependent manner. In addition, mPGES-1 null and heterozygous mice showed a marked reduction of serum IgG against type II collagen, including subclasses IgG1, IgG2a, IgG2b, IgG2c, and IgG3, compared with wild-type mice, which correlated with the reduction in observed inflammatory features. These results demonstrate for the first time that deficiency of mPGES-1 inhibits the development of collagen-induced arthritis, at least in part, by blocking the development of a humoral immune response against type II collagen. Pharmacologic inhibition of mPGES-1 may therefore impact both the inflammation and the autoimmunity associated with human diseases such as rheumatoid arthritis.

Lipid Mediators in Life Science

“…in this model, mPGES-1 deficiency is associated with reduced induction of vascular endothelial cell growth factor (VEGF) in the granulation tissue, implying that mPGES-1-derived PGE 2 , in cooperation with VEGF, contributes to inflammation-associated angiogenesis and thereby to tissue remodeling. in collagen-induced or collagen antibody-induced arthritis models (a mouse model of rheumatoid arthritis), Ptges -/-mice are protected from joint inflammation [27,32,82]. Similar phenotypes have been observed in mice lacking COX-2 [53] or the PGE receptor EP4 [18], thus revealing a metabolic flow of the COX-2/mPGES-1/EP4 pathway in the development of inflammatory arthritis.…”

“…Similar phenotypes have been observed in mice lacking COX-2 [53] or the PGE receptor EP4 [18], thus revealing a metabolic flow of the COX-2/mPGES-1/EP4 pathway in the development of inflammatory arthritis. in addition to the synovial symptoms, defective generation of the humoral immune response is associated with reduced incidence and severity of arthritis in Ptges -/-mice [32], indicating that mPGES-1 also participates in adaptive immunity. in addition, mPGES-1-mediated PGE 2 production by osteoblasts plays a critical role in LPS-induced bone loss associated with inflammation [20].…”

TNF-like Ligand 1A (TL1A) Gene Knockout Leads to Ameliorated Collagen-Induced Arthritis in Mice: Implication of TL1A in Humoral Immune Responses

“…The absolute number and relative percentages of LCMV-specific TNF-a-producing CD4 (gp 61-80 + ) and CD8 cells (gp 33-41 + ) (Supplemental Fig. 1D, 1E), and LCMV-specific IFN-g-producing CD4 (gp 61-80 + ) and CD8 cells (gp [33][34][35][36][37][38][39][40][41] + ) (Supplemental Fig. 1F, 1G) in TL1A KO mice were comparable to those in WT controls.…”

“…1A, the number of CD4 cells and CD8 cells in the spleens on day 8 postinfection presented no significant differences in WT and TL1A KO mice. The absolute numbers and relative percentages of LCMV-specific, tetramerpositive (gp [33][34][35][36][37][38][39][40][41] + and np 396-404 + ) CD8 cells in virus-infected mice were all increased in comparison with uninfected control C57BL/6 mice (data not shown), but there were no significant differences between TL1A KO and WT mice with regard to these parameters (Supplemental Fig. 1B, 1C).…”

“…Each parameter was scored on a 0-3 scale, as previously described, and all four paws (one section per paw) of each animal were scored. The overall score of an animal was the sum of the three parameters of the four paws (41).…”