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Listeriolysin O (LLO) derived from Listeria monocytogenes is highly capable of inducing interleukin (IL)-12, IL-18 and interferon (IFN)-gamma, and facilitates the generation of Th1 cells. We have recently shown that recombinant LLO (rLLO) inhibits generation of ovalbumin (OVA)-specific Th2 immune response by skewing maturation of antigen-specific T cells into Th1 cells. In the present study, we investigated the effect of rLLO on the effector phase of Th2-dependent allergic rhinitis in BALB/c mice sensitized with OVA. In mice sensitized intraperitoneally and challenged intranasally with OVA, nasal allergic symptoms such as sneezing and nose-scratching were observed at a high frequency. A high titre of anti-OVA IgE antibody was detected in sera and a large number of eosinophils migrated into the nasal tissue. However, rLLO treatment during the intranasal challenge inhibited the allergic symptoms, production of anti-OVA IgE antibody and eosinophil infiltration. Though rLLO did not affect antigen-specific cytokine production from splenic CD4(+) T cells, rLLO significantly suppressed OVA-specific IL-4 and IL-5 production from nasal mononuclear cells. We further found that rLLO inhibited the recruitment of CD4(+) T cells in nasal mucosa, and diminished the transcription and cell surface expression of CCR4 on splenic CD4(+) T cells. Moreover, rLLO was able to inhibit the passive cutaneous anaphylaxis reaction mediated by anaphylactic antibodies (IgE and IgG(1)) and mast cells. Taken together, these data showed that rLLO suppresses the effector phase of allergic rhinitis by inhibition of Th2 cell recruitment to nasal mucosa and type I allergic reaction.

Listeriolysin O (LLO), a cholesterol-dependent cytolysin derived from Listeria monocytogenes, is a potent inducer of interleukin (IL)-12, IL-18 and interferon (IFN)-gamma. We have shown that LLO facilitates development of T cells mediating protective immunity against L. monocytogenes through the induction of IFN-gamma production at an early stage. Based on this finding, it is postulated that LLO inhibits differentiation of Th2 cells and the Th2 immune response. By using a murine model of ovalbumin (OVA)-induced allergic rhinitis, we investigated whether LLO has an ability to modulate the Th2-type immune disorder. In mice sensitized intraperitoneally with ovalbumin (OVA)/alum and challenged intranasally with OVA, a large number of eosinophils migrated into the nasal tissue, and high titres of anti-OVA IgE and IgG(1) antibodies were detected in sera. However, LLO treatment during sensitization markedly inhibited the eosinophil infiltration and production of these anti-OVA antibodies. A large number of T cells from mice sensitized and challenged with OVA produced high level of IL-4 and IL-5 but not IFN-gamma after stimulation with OVA. In contrast, OVA-specific IFN-gamma-producing T cells were preferentially induced in mice treated with LLO at the time of sensitization. In the absence of LLO administration, the expression level of GATA-3 and SOCS-3 in CD4(+) T cells was enhanced after sensitization with OVA. LLO treatment resulted in a reduction of GATA-3 and SOCS-3 expressions but induced the transcription of T-bet instead. Taken together, these data show clearly that LLO is capable of inhibiting Th2 immune response by skewing differentiation of antigen-specific T cells into Th1 cells.

IFN-gamma and IL-12 are believed to be important in the host defence against Listeria infection in mice. However, the relationship between these two cytokines and generation of protective immunity remains poorly understood. In the present study, it was found that at least 4 days of immunizing infection were required for the generation of protective immunity against L. monocytogenes. Protective immunity was generated only by immunizing infection with virulent strain. Even repeated injections of avirulent strain failed to induce protective immunity. When the immunizing infection was terminated with antibiotics, generation of protective immunity and IFN-gamma-producing ability was impaired, while expression of IFN-gamma and IL-12 was also impaired. The mutual relationship between IFN-gamma and IL-12 in L. monocytogenes infection was analysed in vitro. After neutralization of IL-12, IFN-gamma production was completely blocked and IFN-gamma expression was also inhibited. In contrast, there was no change of IL-12 expression after neutralization of IFN-gamma. Taking all facts into consideration, it may be concluded that persistent production of IFN-gamma induced by persistent production of IL-12 during immunizing infection is essential for the generation of protective immunity against L. monocytogenes.

Release of O2- and H2O2 from isolated rat liver Kupffer cells was studied by making use of the methods of SOD sensitive ferricytochrome c reduction and horseradish peroxidase catalysed scopoletin oxidation, respectively. Kupffer cells from BCG treated rats showed a 1.8 times significantly higher O2- release and a 2.4 times higher H2O2 release as compared to the controls. Moreover the yield of Kupffer cells was also increased with administration of BCG. These results suggest that Kupffer cells can be immunologically activated to secrete larger amounts of O2- and H2O2.