Summary Vibrio vulnificus, a Gram‐negative estuarine bacterium, is a causative agent of food‐borne diseases, such as life‐threatening septicaemia and wound infection disease. V. vulnificus penetrating into the epithelial barrier stimulates an inflammatory response in the adjacent mucosa. Therefore, interaction between V. vulnificus and epithelial cells is important for understanding of both the immunology of mucosal surfaces and V. vulnificus. In this study, we investigated the effect and action mechanism of V. vulnificus infection on production of interleukin (IL)‐8, a proinflammatory cytokine, in human intestinal epithelial INT‐407 cells. V. vulnificus infection significantly induced IL‐8 production in a time‐ and multiplicity of infection (MOI)‐dependent manner, as determined by human IL‐8 enzyme‐linked immunosorbent assay (ELISA). In addition, V. vulnificus infection significantly increased IL‐8 mRNA levels in INT‐407 cells, indicating that the increased IL‐8 production by V. vulnificus occurred at the transcriptional level. V. vulnificus infection also enhanced IL‐8 gene promoter activity in INT‐407 cells transiently transfected with IL‐8 promoter constructs, but this effect was impaired in INT‐407 cells transfected with IL‐8 promoter constructs deleted or mutated of a κB site. V. vulnificus infection increased the nuclear factor‐kappaB (NF‐κB) binding activity to a κB site and the degradation of IκB‐α protein in a time‐ and a MOI‐dependent manner. Furthermore, BAY11‐7082, an inhibitor of NF‐κB activation, significantly reduced the IL‐8 production, NF‐κB binding activity and IκB‐α degradation induced by V. vulnificus infection. Taken together, these results indicate clearly that V. vulnificus infection significantly induces IL‐8 production in human intestinal epithelial cells via NF‐κB activation.
SUMMARYExposure to cigarette smoke is known to increase the risk of the development of allergic disease. The mechanism is not well understood. In this study, we determined the effect of hydroquinone (HQ), a major metabolite of benzene present in large quantities in cigarette tar, on interleukin-4 (IL-4) production by CD4 + T cells. HQ significantly enhanced IL-4 production by keyhole limpet haemocyanin (KLH)-primed CD4 + T cells in a dose-dependent manner. The enhancing effect of HQ on IL-4 production was maximal at a concentration of 50 mM. It increased the level of IL-4 production approximately 10-fold. HQ enhanced IL-4 mRNA expression and also IL-4 gene promoter activity, suggesting that the enhancing effect of HQ on IL-4 production may occur at the transcriptional level. Furthermore, the injection of KLH-primed mice with HQ resulted in a significant increase in the levels of IL-4 and immunoglobulin E. These findings provide evidence that HQ, a major component of cigarette tar, may enhance allergic immune responses by inducing the production of IL-4 in CD4 + T cells.
SUMMARYThe preferential differentiation of T helper (Th) cells to Th1 or Th2 subsets is important with respect to susceptibility or resistance to particular infections, or to autoimmune diseases and allergic diseases. To more effectively drive immune responses toward antigen-specific Th1 responses, we constructed a mammalian expression vector (pOVA/IFN-c) carrying a hybrid gene in which the ovalbumin (OVA) (a model antigen) cDNA was covalently linked to murine interferon-c (IFN-c) cDNA. Intramuscular injection of BALB/c mice with the pOVA/IFN-c DNA increased both the production of OVA-specific IFN-c by CD4+ T cells and the ratio of anti-OVA immunoglobulin G (IgG)2a to IgG1 isotypes, while the injection with the pOVA alone, or with the mixture of the pOVA and pIFN-c, caused no or little increase. Furthermore, the OVA-specific, Th1 immune responses were dramatically augmented by multiple injections with the pOVA/IFN-c DNA. These studies indicate that the direct linkage of an OVA gene to an IFN-c gene in the expression plasmid is required for efficiently confining the Th1 effects of IFN-c to the OVA-specific cells, and the linkage effect of the OVA/IFN-c DNA can be potentiated by multiple vaccination.
SUMMARYInterferon-gamma (IFN-c) is closely associated with the generation of cell-mediated immunity and resistance to intracellular parasites. Interleukin-18 (IL-18) was known to strongly induce IFN-c production by T cells and natural killer (NK) cells. In order to determine whether injection with DNA encoding IL-18 can stimulate the resistance to Mycobacterium avium complex (MAC) infection, the mature IL-18 cDNA with k leader sequence was cloned under control of the cytomegalovirus (CMV) promoter (TcCMVIL-18) and its effect on MAC infection was investigated in genetically susceptible BALB/c mice. Injection with the TcCMVIL-18 DNA during intranasal infection with MAC resulted in a signi®cant decrease in bacterial load of lung during the entire 8-week observation period, while injection with the TcCMV control DNA did not. Lung cells in mice injected with the TcCMVIL-18 DNA showed persistent production of IFN-c throughout the 8-week period. Furthermore, immunization with the TcCMVIL-18 DNA induced and maintained signi®cantly higher levels of cytotoxic activity and nitric oxide production by lung cells than immunization with the TcCMV control vector. This work suggests that IL-18 DNA vaccination may be useful in the immunotherapeutic or immunoprotection approaches of infections by intracellular parasites such as mycobacteria.
SUMMARYTwo types of T helper (Th) cells ± Th1 and Th2 ± play different roles in protection and immunopathology. The Th1 cell-mediated immune response plays an important role in inducing the host defence against intracellular bacteria and also in cancer immunotherapy. To effectively induce Th1 immune responses, we constructed a mammalian expression plasmid (pAnti-CD3sFv/IL-18) carrying a fusion gene in which anti-CD3 single-chain Fv (sFv) cDNA, the smallest unit of antibody recognizing the CD3 epsilon moiety of the T-cell receptor, was covalently linked to mature interleukin (IL)-18 cDNA. Intramuscular injection of ovalbumin (OVA)-sensitized BALB/c mice with pAnti-CD3sFv/IL-18 DNA ef®ciently increased the production of both OVA-speci®c interferon-g and anti-OVA immunoglobulin G2a, compared to injection with pAnti-CD3sFv DNA. In addition, pAnti-CD3sFv/IL-18 was more ef®cient than a mixture of pAnti-CD3sFv pIL-18 in inducing OVA-speci®c, Th1 immune responses and also in inhibiting OVA-speci®c, IL-4 production. These studies indicate that vaccination with pAnti-CD3sFv/IL-18 fusion DNA ef®ciently induces the Th1 immune response in antigen-sensitized mice.
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