15-Deoxy-Δ^12,14-PGJ₂ inhibits IL-6-induced Stat3 phosphorylation in lymphocytes

15-deoxy-Δ^12,14-PGJ₂ (15d-PGJ₂) is a natural ligand that activates the peroxisome proliferators-activated receptor (PPAR) γ, 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 PPARγ-dependent and -independent mechanisms. Most postulated mechanisms for anti-inflammatory action of PPARγ agonists are involved in inhibiting NF-κB 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 PPARγ. 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 PPARγ-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 PPARγ-independent mechanism. Although cycloheximide reversed 15d-PGJ ₂-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-κB in lymphocytes.