Inhibition of monosodium urate monohydrate crystal-induced acute inflammation by retrovirally transfected prostaglandin D synthase

Arthritis Rheum. 2003 Oct;48(10):2931-41. doi: 10.1002/art.11271.

Abstract

Objective: Hematopoietic prostaglandin D synthase (H-PGDS) is a key enzyme in the production of prostaglandin D and its J series metabolites. We evaluated the antiinflammatory effect of retrovirally transfected H-PGDS in order to investigate the role of H-PGDS in monosodium urate monohydrate (MSU) crystal-induced acute inflammation.

Methods: Expression of endogenous PGDS in a murine air-pouch model of MSU crystal-induced acute inflammation was determined by real-time polymerase chain reaction. H-PGDS complementary DNA (cDNA) was retrovirally transfected into C57BL/6J fibroblasts, and the cells were designated as C57-PGDS cells. Production of prostaglandins by C57-PGDS cells was measured by enzyme immunoassay. The effect of C57-PGDS cells on crystal-induced inflammation was investigated.

Results: Injection of the crystals caused a rapid decrease in H-PGDS expression by infiltrating cells and by the soft tissues around the air pouches. In contrast, expression of interleukin-1beta (IL-1beta) and macrophage inflammatory protein 2 (MIP-2) as well as cellular infiltration were significantly increased during the early stage of inflammation. C57-PGDS cells, but not control cells, produced an increased amount of PGD(2) in vitro, but suppressed production of PGE(2). Injection of C57-PGDS cells into air pouches inhibited cellular infiltration and MIP-2 and IL-1beta expression.

Conclusion: In this murine air-pouch model of MSU crystal-induced inflammation, retrovirally transfected H-PGDS cDNA could reduce cellular infiltration, at least partly by inhibiting MIP-2 and IL-1beta. These findings suggest that gene therapy with H-PGDS may be useful for treating inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Arthritis, Gouty / immunology
  • Arthritis, Gouty / therapy*
  • Cell Line, Tumor
  • Chemokine CXCL2
  • Chemokines / genetics
  • Crystallization
  • Disease Models, Animal
  • Fibroblasts / cytology
  • Gene Expression Regulation, Enzymologic
  • Genetic Therapy*
  • Interleukin-1 / genetics
  • Intramolecular Oxidoreductases / genetics*
  • Leukemia, Basophilic, Acute
  • Lipocalins
  • Macrophages / cytology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / metabolism
  • Rats
  • Retroviridae / genetics*
  • Transfection
  • Uric Acid / chemistry
  • Uric Acid / immunology*

Substances

  • Chemokine CXCL2
  • Chemokines
  • Cxcl2 protein, mouse
  • Interleukin-1
  • Lipocalins
  • Uric Acid
  • 9-deoxy-delta-9-prostaglandin D2
  • Intramolecular Oxidoreductases
  • prostaglandin R2 D-isomerase
  • Prostaglandin D2