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


CONCLUSIONS
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.
Murakami
Yousuke
Y
Kitasato University School of Medicine, Sagamihara, Japan.
Akahoshi
Tohru
T
Hayashi
Izumi
I
Endo
Hirahito
H
Hashimoto
Atsushi
A
Kono
Shizuka
S
Kondo
Hirobumi
H
Kawai
Shinichi
S
Inoue
Matsuhisa
M
Kitasato
Hidero
H
D000208:Acute Disease; D000818:Animals; D015210:Arthritis, Gouty / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics; D003460:Crystallization; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy; D007375:Interleukin-1 / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D015471:Leukemia, Basophilic, Acute; D054834:Lipocalins; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D012190:Retroviridae / Q000235:genetics*; D014162:Transfection; D014527:Uric Acid / Q000737:chemistry / Q000276:immunology*
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D007375:Interleukin-1; D054834:Lipocalins; D014527:Uric Acid; C037112:9-deoxy-delta-9-prostaglandin D2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2