15-deoxy-Delta 12,14-PGJ2 induces IL-8 production in human T cells by a mitogen-activated protein kinase pathway.
Mast cells, platelets, and some macrophages are abundant sources of PGD(2) and its active metabolite 15-deoxy-Delta(12,14)-PGJ(2) (15-d-PGJ(2)). The lipid mediator 15-d-PGJ(2) regulates numerous processes, including adipogenesis, apoptosis, and inflammation. The 15-d-PGJ(2) has been shown to both inhibit as well as induce the production of inflammatory mediators such as TNF-alpha, IL-1beta, and cyclooxygenase, mostly occurring via a nuclear receptor called peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Data concerning the effects of 15-d-PGJ(2) 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-PGJ(2) can regulate the production of IL-8 in T cells in unknown. Interestingly, 15-d-PGJ(2) treatment of unstimulated T cells induces cell death. In contrast, in activated human T lymphocytes, 15-d-PGJ(2) does not kill them, but induces the synthesis of IL-8. In this study, we report that 15-d-PGJ(2) induced a significant increase in both IL-8 mRNA and protein from activated human T lymphocytes. The induction of IL-8 by 15-d-PGJ(2) did not occur through the nuclear receptor PPAR-gamma, as synthetic PPAR-gamma agonists did not mimic the IL-8-inducing effects of 15-d-PGJ(2). The mechanism of IL-8 induction was through a mitogen-activated protein kinase and NF-kappaB pathway, as inhibitors of both systems abrogated IL-8 protein induction. Therefore, 15-d-PGJ(2) 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-PGJ(2) 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-PGJ(2).
Harris
Sarah G
SG
Cancer Center, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Smith
Roger S
RS
Phipps
Richard P
RP
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D015237:Dinoprost / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000276:Adjuvants, Immunologic; D018836:Inflammation Mediators; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D015237:Dinoprost; D015230:Prostaglandin D2