Rapid induction of peroxisome proliferator-activated receptor gamma expression in human monocytes by monosodium urate monohydrate crystals.
OBJECTIVE
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear hormone receptor superfamily and functions as a key regulator of lipid and glucose metabolism, atherosclerosis, and inflammatory responses. This study was undertaken to evaluate the biologic role of PPAR gamma in self-limiting episodes of acute gouty arthritis. To do this, we investigated PPAR gamma expression by monosodium urate monohydrate (MSU) crystal-stimulated monocytes, and we studied the effects of PPAR gamma ligands on crystal-induced acute inflammation.


METHODS
PPAR gamma expression by MSU crystal-stimulated human peripheral blood mononuclear cells was determined by reverse transcription-polymerase chain reaction and immunostaining. Expression of CD36 on monocytes was detected by flow cytometric analysis. The effects of PPAR gamma ligands on in vitro crystal-induced cytokine production and on in vivo cellular infiltration during crystal-induced acute inflammation were also investigated.


RESULTS
MSU crystals rapidly and selectively induced PPAR gamma expression by monocytes. Gene expression was detected as early as 2 hours, and maximum expression was observed at 4 hours after stimulation. The induced PPAR gamma was functional, since a PPAR gamma ligand was able to up-regulate CD36 expression on monocytes. A natural ligand of PPAR gamma, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15deoxy-PGJ(2)), significantly reduced the crystal-induced production of cytokines by monocytes. Indomethacin inhibited cytokine production only at high concentrations, and an antidiabetic thiazolidinedione (troglitazone) failed to exert significant effects. Administration of troglitazone and 15deoxy-PGJ(2) significantly prevented cellular accumulation in a mouse air-pouch model of MSU crystal-induced acute inflammation.


CONCLUSIONS
Rapid induction of PPAR gamma expression on monocytes by MSU crystals may contribute, at least in part, to the spontaneous resolution of acute attacks of gout.
Akahoshi
Tohru
T
Department of Laboratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. akahoshi@med.kitasato-u.ac.jp
Namai
Rie
R
Murakami
Yousuke
Y
Watanabe
Megumi
M
Matsui
Toshimichi
T
Nishimura
Akito
A
Kitasato
Hidero
H
Kameya
Toru
T
Kondo
Hirobumi
H
D000208:Acute Disease; D000818:Animals; D015210:Arthritis, Gouty / Q000276:immunology* / Q000503:physiopathology*; D018955:CD36 Antigens / Q000235:genetics; D003460:Crystallization; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014527:Uric Acid / Q000737:chemistry / Q000494:pharmacology*
D018955:CD36 Antigens; D016207:Cytokines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014527:Uric Acid