Exp Mol Med.  2005 Jun;37(3):179-185.

15-Deoxy-delta12,14-PGJ2inhibits IL-6-induced Stat3 phosphorylation in lymphocytes

• Kim HJ
• Rho YH
• Choi SJ
• Lee YH
• Cheon HJ
• Um JW
• Sohn J
• Song GG
• Ji JD

Abstract

15-deoxy-delta12,14-PGJ2(15d-PGJ2) 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-PGJ2 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-PGJ2 in lymphocytes and also examined whether the inhibition of IL-6 signaling is dependent of PPARgamma. 15d-PGJ2 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-PGJ2. Other PPARgamma-agonists, such as troglitazone and ciglitazone, did not inhibit IL-6 signaling, indicating that 15d-PGJ2 affect the IL-6-induced Jak-Stat signaling pathway via PPARgamma-independent mechanism. Although cycloheximide reversed 15d-PGJ2-mediated inhibition of Stat3 activation, actinomycin D had no effect on 15d-PGJ2-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-PGJ2 specifically inhibit Jak-Stat signaling pathway in lymphocytes, and suggest that 15d-PGJ2 may regulate inflammatory reactions through the modulation of different signaling pathway other than NF-kappaB in lymphocytes.

Keyword

15-deoxy-delta(12,14)-prostaglandin J2; Interleukin-6; inflammation mediators; lymphocytes; PPARgammar; Stat1 protein; Stat3 protein

MeSH Terms

Arthritis, Rheumatoid/metabolism/pathology
Chromans/pharmacology
Cycloheximide/pharmacology
DNA-Binding Proteins/*metabolism
Dactinomycin/pharmacology
Gene Expression Regulation
Humans
Hypoglycemic Agents/pharmacology
Interleukin-6/*pharmacology
Jurkat Cells/metabolism/pathology
Lymphocytes/cytology/*drug effects/*metabolism
NF-kappa B/metabolism
PPAR gamma/metabolism
Phosphorylation
Prostaglandin D2/*analogs & derivatives/pharmacology
Protein Synthesis Inhibitors/pharmacology
Research Support, Non-U.S. Gov't
*Signal Transduction
Thiazolidinediones/pharmacology
Trans-Activators/*metabolism