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

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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.