15-Deoxy-Δ12,1412,14-PGJ2 Induces IL-8 Production in Human T Cells by a Mitogen-Activated Protein Kinase Pathway

Abstract

Mast cells, platelets, and some macrophages are abundant sources of PGD2 and its active metabolite 15-deoxy-Δ12,14-PGJ2 (15-d-PGJ2). The lipid mediator 15-d-PGJ2 regulates numerous processes, including adipogenesis, apoptosis, and inflammation. The 15-d-PGJ2 has been shown to both inhibit as well as induce the production of inflammatory mediators such as TNF-α, IL-1β, and cyclooxygenase, mostly occurring via a nuclear receptor called peroxisome proliferator-activated receptor-γ (PPAR-γ). Data concerning the effects of 15-d-PGJ2 on human T cells and immune regulation are sparse. IL-8, a cytokine with both chemotactic and angiogenic effects, is produced by T lymphocytes following activation. Whether 15-d-PGJ2 can regulate the production of IL-8 in T cells in unknown. Interestingly, 15-d-PGJ2 treatment of unstimulated T cells induces cell death. In contrast, in activated human T lymphocytes, 15-d-PGJ2 does not kill them, but induces the synthesis of IL-8. In this study, we report that 15-d-PGJ2 induced a significant increase in both IL-8 mRNA and protein from activated human T lymphocytes. The induction of IL-8 by 15-d-PGJ2 did not occur through the nuclear receptor PPAR-γ, as synthetic PPAR-γ agonists did not mimic the IL-8-inducing effects of 15-d-PGJ2. The mechanism of IL-8 induction was through a mitogen-activated protein kinase and NF-κB pathway, as inhibitors of both systems abrogated IL-8 protein induction. Therefore, 15-d-PGJ2 can act as a potent proinflammatory mediator in activated T cells by inducing the production of IL-8. These findings show the complexity with which 15-d-PGJ2 regulates T cells by possessing both pro- and anti-inflammatory properties depending on the activation state of the cell. The implications of this research also include that caution is warranted in assigning a solely anti-inflammatory role for 15-d-PGJ2.

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

“…Because PPAR-␥ gene and protein expressions are up-regulated and its protein localization to the nucleus is promoted by AM/AMBP-1, we propose that this is a major pathway of the anti-inflammatory effect of AM/AMBP-1. We have previously shown that PPAR-␥ activation is in fact responsible for the down-regulation of LPS-induced TNF-␣ release in inhibition studies using GW9662, a PPAR-␥ selective antagonist (51). In this model, the AM/AMBP-1-mediated up-regulation of PPAR-␥ seems to play a greater role than the LPS-mediated suppression of PPAR-␥ in the regulation of TNF-␣ response.…”

15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells

“…Similarly, Ward et al (2002) recently showed that 15-PGJ 2 exploits PPARg-independent inhibition of NF-kB activation to induce caspase-dependent apoptosis in granulocytes. Other mediators that have been implicated in PPARg-independent properties of 15-PGJ 2 and can potentially have a similar function in cancer cells include AP-1 (Boyault et al, 2001), MAP kinase (Harris et al, 2002;Lennon et al, 2002), and reactive oxygen species (Li et al, 2001;Lennon et al, 2002). The latter has been shown to act as intermediates for the induction of apoptosis caused by 15-PGJ 2 in human myofibroblasts (Li et al, 2001).…”

The Cyclopentenone-Type Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits CD95 Ligand Gene Expression in T Lymphocytes: Interference with Promoter Activation Via Peroxisome Proliferator-Activated Receptor-γ-Independent Mechanisms

“…Recently, a PPAR␥-mediated inhibition of NF-B together with NF-AT and AP-1 DNA binding activity and repression of the transactivation driven by these transcription factors has been described in human T cells that correlated with inhibition of proliferation, IL-2 production, and promoter activation in the presence of synthetic and natural PPAR␥ activators including 15d-PGJ 2 (67, 68 2 has been shown to induce IL-8 production via activation of mitogen-activated protein kinases together with the NF-B and AP-1 transcription factors (69). In this case the effect was not related to PPAR␥, as synthetic PPAR␥ agonists did not mimic the 15d-PGJ 2 -mediated IL-8 induction.…”