Prostaglandin E2 Induces Interleukin-8 Gene Transcription by Activating C/EBP Homologous Protein in Human T Lymphocytes
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.
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- "Plasmid Constructs and full-length HBV DNA Genomes Plasmid constructs containing the full-length wild-type (wtIL-8 LUC) or truncated IL-8 promoters [IL-8 AP-1 mutant (IL-8-mAP1), IL-8 C/EBP mutant (IL-8-mC/EBP), IL-8 NF-kB mutant (IL-8-mNF- kB), and IL-8 double mutant for C/EBP and NF-kB (IL-8-C/EBP- NFkB)] controlling the expression of the luciferase gene were generated as described previously (Caristi et al., 2005; Venza et al., 2007). Monomeric linear full-length wild type (WT) and HBx mutant HBV genomes of genotype A (WTHBV-A and mutHBxHBV-A, respectively) were released from the pCR.HBV.A.EcoRI (Pollicino et al., 2006) and pCR.mtHBx.A.EcoRI (Belloni et al., 2009) plasmids using EcorRI-PvuI restriction enzymes (New England Biolabs GmbH, Frankfurt, Germany). "
ABSTRACT: High levels of serum interleukin-8 (IL-8) have been detected in chronic hepatitis B (CHB) patients during episodes of hepatitis flares. We investigated whether hepatitis B virus (HBV) may directly induce IL-8 production and whether IL-8 may antagonize interferon-alpha (IFN-α) antiviral activity against HBV. We showed that CHB patients had significantly higher IL-8 levels both in serum and in liver tissue than controls. In HBV-replicating HepG2 cells, IL-8 transcription was significantly activated. AP-1, C/EBP and NF-kB transcription factors were concurrently necessary for maximum IL-8 induction. Moreover, HBx viral protein was recruited onto the IL-8 promoter and this was paralleled by IL8-bound histone hyperacetylation and by active recruitment of transcriptional coactivators. Inhibition of IL-8 increases the antiviral activity of IFN-α against HBV. Our results indicate that HBV activates IL-8 gene expression by targeting the epigenetic regulation of the IL-8 promoter and that IL-8 may contribute to reduce HBV sensitivity to IFN-α.Virology 07/2013; 444(1-2). DOI:10.1016/j.virol.2013.06.028 · 3.32 Impact Factor
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- "An indirect pro-inflammatory role for PGE2 in human T lymphocytes was shown to be mediated by the induction of IL-8 (CXCL8) gene transcription following activation of C/EBP homologous protein.106 IL-8 (CXCL8) thus produced by T cells was then shown to mediate neutrophil recruitment and sustain inflammation.106 "
ABSTRACT: Our understanding of the key players involved in the differential regulation of T-cell responses during inflammation, infection and auto-immunity is fundamental for designing efficient therapeutic strategies against immune diseases. With respect to this, the inhibitory role of the lipid mediator prostaglandin E(2) (PGE(2)) in T-cell immunity has been documented since the 1970s. Studies that ensued investigating the underlying mechanisms substantiated the suppressive function of micromolar concentrations of PGE(2) in T-cell activation, proliferation, differentiation and migration. However, the past decade has seen a revolution in this perspective, since nanomolar concentrations of PGE(2) have been shown to potentiate Th1 and Th17 responses and aid in T-cell proliferation. The understanding of concentration-specific effects of PGE(2) in other cell types, the development of mice deficient in each subtype of the PGE(2) receptors (EP receptors) and the delineation of signalling pathways mediated by the EP receptors have enhanced our understanding of PGE(2) as an immune-stimulator. PGE(2) regulates a multitude of functions in T-cell activation and differentiation and these effects vary depending on the micro-environment of the cell, maturation and activation state of the cell, type of EP receptor involved, local concentration of PGE(2) and whether it is a homeostatic or inflammatory scenario. In this review, we compartmentalize the various aspects of this complex relationship of PGE(2) with T lymphocytes. Given the importance of this molecule in T-cell activation, we also address the possibility of using EP receptor antagonism as a potential therapeutic approach for some immune disorders.Immunology and Cell Biology 09/2011; 90(6):579-86. DOI:10.1038/icb.2011.75 · 4.15 Impact Factor
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- "PGE 2 was reported to induce the accumulation of IL-8 mRNA and protein production in human colonic epithelial cells (Yu and Chadee, 1998). PGE 2 induces IL-8 mRNA transcription through PGE 2 receptor 1-and 4-dependent signal transduction pathway in human T cells (Caristi et al., 2005). IL-8 is well known for its angiogenesis capability in many human cancers. "
ABSTRACT: Cyclooxygenase-2 (COX-2) is critical for tumor formation, angiogenesis, metastasis, and prognosis. In this study, the role of COX-2 in antiapoptosis, tumorigenesis, and angiogenesis of human basal cell carcinoma (BCC) cells was investigated. Transfection of COX-2 constitutive expression vector into a BCC cell line yielded several overexpressing clones. All transfectants demonstrated remarkable resistance to ultraviolet B-induced apoptosis (confirmed by flow cytometry analysis, morphological change, and DNA fragmentation). Immunoblot analysis revealed marked increases in apoptosis-regulated genes Mcl-1 and Bcl-2. A 10-fold concentrated conditioned medium from COX-2-overexpressing BCC cells exhibited higher angiogenic activity in Matrigel plug and human umbilical vein endothelial cell tube formation assay. Cells exhibited increased levels of vascular endothelial growth factor-A (VEGF-A) mRNA and protein, and secreted VEGF-A and basic fibroblast growth factor (bFGF). COX-2-specific small interfering RNA markedly reduced the secreted species. After 7 weeks of inoculation, the tumor volume of COX-2-overexpressing cells in severe combined immunodeficient mice was significantly greater than that of vector control cells. Immunohistochemical analysis of CD31-positive vessels revealed a two-fold increase in microvessel density in COX-2 tumors, compared to control vector tumors. Our data indicate that Mcl-1 and Bcl-2, as well as VEGF-A and bFGF, are downstream effectors of COX-2-induced antiapoptosis and angiogenesis, respectively.Journal of Investigative Dermatology 06/2006; 126(5):1143-51. DOI:10.1038/sj.jid.5700191 · 7.22 Impact Factor