ABSTRACT
1. Hyper-induction of cytokines and chemokines was found in human blood macrophages infected with the avian influenza H5N1 and H9N2/G1 viruses, as compared to those infected with human influenza H1N1 virus. 2. IRF3 played a significant role in the hyperinduction of cytokines including IFN-ß, IFN-λ1,IFN-α subtypes, MCP-1, and TNF-α, and also played a part in subsequent cytokine-induced cell signalling cascades. 3. Compared with H1N1 viruses, avian influenza viruses including H5N1/97 and its precursors triggered a caspase-mediated but delayed apoptotic response in human macrophages. 4. Therapies that can minimise immunopathology-associated dysregulation of innate immunity without impairing effective host defence may be valuable adjuncts to antiviral therapy.
Subject(s)
Apoptosis , Cytokines/genetics , Influenza A Virus, H5N1 Subtype , Influenza, Human/metabolism , Interferon Regulatory Factor-3/metabolism , Macrophages/metabolism , RNA, Messenger/metabolism , Caspase 3/metabolism , Cells, Cultured , Cytokines/biosynthesis , Gene Expression Regulation , Humans , Influenza A Virus, H1N1 Subtype , Interferon Regulatory Factor-3/genetics , Interferon-beta/biosynthesis , Interferon-beta/genetics , Interferons , Interleukins/biosynthesis , Interleukins/genetics , Macrophages/enzymology , Macrophages/virology , Poly(ADP-ribose) Polymerases/metabolism , RNA, Small Interfering , Transcription Factors/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/genetics , Up-Regulation/geneticsSubject(s)
Immunotherapy/methods , Interferon-gamma/pharmacology , Interleukin-10/metabolism , Monocytes/immunology , Mycobacterium bovis/immunology , Tuberculosis/immunology , Tuberculosis/therapy , Cells, Cultured , Gene Expression Regulation/immunology , Humans , Interleukin-10/immunology , Interleukin-12/pharmacology , Monocytes/microbiology , eIF-2 Kinase/immunologyABSTRACT
Epstein--Barr virus latent infection is associated with human malignancies including Burkitt's lymphoma, gastric carcinoma and the highly invasive nasopharyngeal carcinoma (NPC). Increased expression of EBV latent membrane protein 1, LMP1, is correlated with tumor progression and metastasis in NPC. LMP1 induces cellular proteins including cytokines and matrix metalloproteinases (e.g., MMP1, MMP2 and MMP9). MMPs are endopeptidases involved in the degradation of extracellular matrix proteins; and their upregulation in cancer implicates their potential role in tumor metastasis. In light of the role of LMP1 in cytokine dysregulation and the fact that MMPs are regulated by cytokines, we examined whether LMP1 promotes NPC metastasis via the induction of MMPs. To delineate the oncogenic role of LMP1 in NPC, we first investigated the induction of MMP1, MMP2, MMP3 and MMP9 in LMP1-positive NPC tumor samples (n=15) by quantitative RT-PCR. We showed a significant induction of MMP1 and MMP3 transcripts in the EBV LMP1-positive NPC tissues, compared with biopsies obtained from the adjacent non-tumor tissues. To investigate the role of LMP1 in MMP expression in NPC, we cloned the LMP1 gene from NPC samples and transiently expressed it in MRC5 cells (human lung fibroblasts). Following transfection, a time-dependent elevation of endogenous MMP3 expression was found in the LMP1-transfectants by quantitative RT-PCR and Western analysis. Taken together, we observed that MMP3 is upregulated in LMP1-positive NPC tumors and LMP1-expression in fibroblasts is associated with MMP3 and cytokine expression. Our results suggest that LMP1 may contribute to invasiveness of NPC cells via the expression of MMP3 in fibroblasts.
