Prostaglandin E2 induces interleukin-8 gene transcription by activating C/EBP homologous protein in human T lymphocytes.

Department of Experimental Pathology and Microbiology, University of Messina, 98125 Messina, Italy.
Journal of Biological Chemistry (Impact Factor: 4.65). 05/2005; 280(15):14433-42. DOI: 10.1074/jbc.M410725200
Source: PubMed

ABSTRACT The effect of prostaglandin E(2) (PGE(2)) in regulating the synthesis of the pro-inflammatory chemokine interleukin-8 (IL-8) in T lymphocytes is not yet defined, even though it may reduce or enhance IL-8 synthesis in other cell types. Here, we demonstrate that, in human T cells, PGE(2) induced IL-8 mRNA transcription through prostaglandin E(2) receptors 1- and 4-dependent signal transduction pathways leading to the activation of the transcription factor C/EBP homologous protein (CHOP), never before implicated in IL-8 transcription. Several kinases, including protein kinase C, Src family tyrosine kinases, phosphatidylinositol 3-kinase, and p38 MAPK, were involved in PGE(2)-induced CHOP activation and IL-8 production. The transactivation of the IL-8 promoter by CHOP was NF-kappaB-independent. Our data suggest that PGE(2) acts as a potent pro-inflammatory mediator by inducing IL-8 gene transcription in activated T cells through different signal transduction pathways leading to CHOP activation. These findings show the complexity with which PGE(2) regulates IL-8 synthesis by inhibiting or enhancing its production depending on the cell types and environmental conditions.

  • [Show abstract] [Hide abstract]
    ABSTRACT: During bacterial infection, hematopoietic stem and progenitor cells (HSPCs) differentiate into polymorphonuclear leukocytes (PMNs) in the bone marrow (BM). We reported that HSPCs recruited to S. aureus-infected skin wounds in mice, undergo granulopoiesis, while others have demonstrated their differentiation in vitro after TLR2/MyD88 stimulation. Here, we examined this pathway in HSPC trafficking and granulopoiesis within S. aureus-infected wounds. Lineage(-) HSPCs from TLR2- or MyD88-deficient mice injected into infected wounds of wild type (WT) mice exhibited impaired granulopoiesis. However, HSPCs from WT mice produced similar numbers of PMN whether transferred into wounds of TLR2-, MyD88-deficient or WT mice. Prostaglandin E2 (PGE2), which stimulates HSPC survival and proliferation, was produced by HSPCs after TLR2 stimulation, suggesting that TLR2/MyD88 activation promotes granulopoiesis in part by production and autocrine activity of PGE2. Pretreatment of TLR2- or MyD88-deficient HSPCs with PGE2 rescued granulocytic differentiation in vivo. Finally, we demonstrate that BM-derived lin(-)/Sca-1(+)/c-kit(+) (LSK) cells produced PGE2 and underwent granulopoiesis after TLR2 stimulation. LSK cells deficient in TLR2 or MyD88 produced PMN after PGE2 treatment when transferred into uninfected wounds. We conclude that granulopoiesis in S. aureus-infected wounds is induced by TLR2/MyD88 activation of HSPCs through a mechanism that involves autocrine production and activity of PGE2.
    Blood 07/2013; · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have suggested that mast cells have critical roles in angiogenesis. However, the detailed mechanism by which mast cells contribute to angiogenesis is not yet clearly understood, especially in response to proinflammatory cytokines. In this study, we showed that the proinflammatory cytokine IL-1beta induces the synthesis of IL-8, a potent angiogenic factor, in human mast cells via the leukotriene B(4) receptor (BLT)2. We also characterized the BLT2 downstream signaling pathway and determined that BLT2-mediated IL-8 synthesis involves the upregulation of Nox1, a member of the NADPH oxidase family, Nox1-dependent reactive oxygen species generation and the subsequent activation of the redox-sensitive transcription factor NF-kappaB. For instance, knockdown of BLT2 and Nox1 with specific small interfering RNA, treatment with a specific BLT2 antagonist, LY255283, or treatment with a potential Nox inhibitor, diphenylene iodonium, suppressed IL-1beta-induced IL-8 synthesis. We found that the conditioned media collected from IL-1beta-treated human mast cell line HMC-1 had significantly enhanced angiogenic activity that could be dramatically attenuated by either small interfering RNA knockdown of BLT2 or treatment with neutralizing Ab to IL-8. Finally, the experiments were repeated using human primary cord blood-derived mast cells, and the results were clearly reproduced. Taken together, our results suggest that BLT2-Nox1-reactive oxygen species-dependent pathway plays a role in promoting the secretion of IL-8 from human mast cells in response to the proinflammatory cytokine IL-1beta, thus contributing to angiogenesis.
    The Journal of Immunology 03/2010; 184(7):3946-54. · 5.52 Impact Factor
  • Source