15-Deoxy-delta12,14-PGJ2 inhibits IL-6-induced Stat3 phosphorylation in lymphocytes.
15-deoxy-delta(12,14)-PGJ(2)(15d-PGJ(2)) is a natural ligand that activates the peroxisome proliferators-activated receptor (PPAR) gamma, a member of nuclear receptor family implicated in regulation of lipid metabolism and adipocyte differentiation. Recent studies have shown that 15d-PGJ(2) is the potent anti-inflammatory agent functioning via PPARgamma-dependent and -independent mechanisms. Most postulated mechanisms for anti-inflammatory action of PPARgamma agonists are involved in inhibiting NF-kappaB signaling pathway. We examined the possibility that IL-6 signaling via the Jak-Stat pathway is modulated by 15d-PGJ(2) in lymphocytes and also examined whether the inhibition of IL-6 signaling is dependent of PPARgamma. 15d-PGJ(2) blocked IL-6 induced Stat1 and Stat3 activation in primary human lymphocytes, Jurkat cells and immortalized rheumatoid arthritis B cells. Inhibition of IL-6 signaling was induced rapidly within 15 min after treatment of 15d-PGJ(2). Other PPARgamma-agonists, such as troglitazone and ciglitazone, did not inhibit IL-6 signaling, indicating that 15d-PGJ(2) affect the IL-6-induced Jak-Stat signaling pathway via PPARgamma-independent mechanism. Although cycloheximide reversed 15d-PGJ(2)-mediated inhibition of Stat3 activation, actinomycin D had no effect on 15d-PGJ(2)-mediated inhibition of IL-6 signaling, indicating that inhibition of IL-6 signaling occur independent of de novo gene expression. These results show that 15d-PGJ(2) specifically inhibit Jak-Stat signaling pathway in lymphocytes, and suggest that 15d-PGJ(2) may regulate inflammatory reactions through the modulation of different signaling pathway other than NF-kappaB in lymphocytes.
Kim
Hyo Jin
HJ
Department of Microbiology and Immunology, College of Medicine, Korea University, Seoul 136-705, Republic of Korea.
Rho
Young Hee
YH
Choi
Seong Jai
SJ
Lee
Young Ho
YH
Cheon
HyeonJoo
H
Um
Jun Won
JW
Sohn
Jeongwon
J
Song
Gwan Gyu
GG
Ji
Jong Dae
JD
D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002839:Chromans / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D019169:Jurkat Cells / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D015850:Interleukin-6; D016328:NF-kappa B; D047495:PPAR gamma; D011500:Protein Synthesis Inhibitors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D045162:Thiazolidinediones; D015534:Trans-Activators; D003609:Dactinomycin; D003513:Cycloheximide; D000077288:Troglitazone; D015230:Prostaglandin D2; C039671:ciglitazone