15d-PGJ 2 Upregulates Synthesis of IL-8 in Endothelial Cells Through Induction of Oxidative Stress

Abstract

15-Deoxy-Δ^12,14-prostaglandin-J₂ (15d-PGJ₂) is a cyclopentenone prostaglandin regarded as antiinflammatory mediator, which can act through peroxisome proliferator–activated receptor-γ (PPARγ) or through G protein–coupled surface receptors. It has been demonstrated that 15d-PGJ₂ potently increases the generation of interleukin-8 (IL-8) in human microvascular endothelial cells (HMEC-1s); however, the mechanism of this induction is not known. The aim of the study was to find the pathway involved in 15d-PGJ₂–mediated IL-8 stimulation. Our data confirmed that the effect of 15d-PGJ₂ is independent of PPARγ. For the first time, we excluded the activation of G proteins and the contribution of G protein–coupled surface receptors in endothelial cells treated with 15d-PGJ₂. Instead, we demonstrated that stimulation of IL-8 involved induction of oxidative stress, activation of p38 kinases, and increase in stability of IL-8 mRNA. Upregulation of IL-8 promoter, although measurable, seemed to play a less-pronounced role. Additionally, our results indicate the involvement of cAMP elevation and may suggest a role for ATF2 transcription factor. Concomitant induction of heme oxygenase-1 in HMEC-1s did not influence the synthesis of IL-8. In summary, we showed that 15d-PGJ₂, acting through oxidative stress, may exert proinflammatory effects. The upregulation of IL-8 is mostly associated with p38-mediated stabilization of mRNA.