Our previous study showed that gamma interferon (IFN-␥), a T-helper 1 (Th1)-type cytokine, plays a detrimental role in

There have been no studies on the susceptibility and host immune responses to an intranasal infection with Listeria monocytogenes. In this study, we compared the susceptibilities and cytokine responses between intranasal and intravenous infections with L. monocytogenes in mice. Moreover, we compared efficiency of acquisition of host resistance to L. monocytogenes infection between intranasally and intravenously immunized mice because an intranasal immunization of vaccines is reportedly available for induction of adaptive immunity against various infectious pathogens. The susceptibility to an intranasal infection with L. monocytogenes was markedly lower than that to the intravenous infection. The bacterial growth in the lungs, spleens, and livers was substantially similar between intranasally and intravenously infected mice. Titers of endogenous gamma interferon (IFN-␥) and tumor necrosis factor-␣ (TNF-␣) in the spleens, livers, and lungs were parallel to bacterial numbers in each organ of mice during intranasal infection and intravenous infection. IFN-␥-deficient mice and TNF-␣-deficient mice were highly susceptible to intranasal infection as well as intravenous infection.Susceptibilities to intranasal and intravenous L. monocytogenes infection were the same in these cytokinedeficient mice. These results suggest that both IFN-␥ and TNF-␣ play critical roles in host resistance to intranasal L. monocytogenes infection as well as the intravenous infection. Acquisition of host resistance to intravenous and intranasal L. monocytogenes infection was induced in intranasally immunized mice as well as intravenously immunized mice, suggesting that intranasal immunization is effective for prevention of a systemic infection with L. monocytogenes.

Listeria monocytogenes promotes the induction of the T-helper 1 (Th1) cell response, while ovalbumin (OVA) induces a Th2 cell response and allergic reactions, such as airway hyperreactivity and immunoglobulin E (IgE) production. When mice were immunized with OVA on day 7 after L. monocytogenes infection, eosinophilia in bronchoalveolar lavage and the production of total IgE, OVA-specific IgE, interleukin-4 (IL-4), and IL-5 in the circulation were markedly suppressed. Cytokine responses, including IL-4, IL-5, IL-10, IL-13, and gamma interferon, to OVA were decreased in the spleen cell cultures obtained from OVA-immunized mice that had been infected with L. monocytogenes. Conversely, when OVA-immunized mice were infected with L. monocytogenes, conversion from the nonlethal infection to the lethal infection occurred. Host resistance to L. monocytogenes infection in OVA-immunized mice was enhanced by the administration of anti-IL-10 monoclonal antibody. The present study indicates that striking interference is observed between Th1-inducing L. monocytogenes infection and Th2-driven OVA-induced airway hyperreactivity. Antigen-specific CD4ϩ T-helper (Th)-cell responses can be divided into two types, based on cytokine production and effector function (1). Differentiation of Th1 cells, which can produce interleukin-2 (IL-2), gamma interferon (IFN-␥), and lymphotoxin, is driven by IL-12, while differentiation of Th2 cells, which can produce IL-4, IL-5, IL-10, and IL-13, is driven by IL-4. Listeria monocytogenes, a facultative intracellular bacterium, induces the Th1 cell response in the infected host (14); IFN-␥ plays a critical role in antilisterial resistance (11), while IL-4 and IL-10 inhibit antilisterial resistance (3,8).Asthma is a disease caused by a type I allergic response to allergens and characterized by chronic airway inflammation, with recruitment of eosinophils. Th2 cells secreting IL-4, IL-5, and IL-13 have an important role in the development of asthma (12, 23). Previous reports indicated that IFN-␥-dominated immune responses to viral or mycobacterial infection in childhood are associated with a reduced incidence of asthma (25,26). Recently, a mouse model of ovalbumin (OVA)-induced allergic airway hyperresponsiveness reportedly revealed a reduction in allergic responses, including eosinophilic airway inflammation and serum immunoglobulin E (IgE) production, as a result of infection with Mycobacterium bovis BCG (4) or injection of killed M. vaccae (29) or killed L. monocytogenes (10), which induces Th1 cells (24). Therefore, we were interested in investigating the interaction between Th2-polarized OVA-induced airway hyperreactivity and Th1-polarized L. monocytogenes infection in mice.In this study, female C57BL/6 mice, 6 to 8 weeks old, were purchased from CLEA Japan, Inc., Tokyo, Japan. All animals were maintained under specific-pathogen-free conditions at the Institute for Animal Experiments, School of Medicine, Hirosaki University. Data were expressed as means and standard deviations (SD), and the Wilcox...

It has been demonstrated that endogenous cytokines including gamma interferon (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) play protective roles but that IL-4 and IL-10 play detrimental roles in nonlethal Listeria monocytogenes infection in mice. In this paper, we studied the roles of endogenous cytokines in a lethal infection with L. monocytogenes in mice. TNF-alpha and IL-6 titres in the bloodstreams, spleens and livers paralleled bacterial numbers in the organs, and both these cytokines and the bacterial numbers peaked just before the mice died. The high titres of TNF-alpha notably detected in the circulation in lethal infection were different from those in nonlethal infection. The maximum production of IFN-gamma was observed before the peaks of TNF-alpha and IL-6, and IFN-gamma almost disappeared from the bloodstreams and organs just before the mice died. No notable difference of IFN-gamma titres between lethal infection and nonlethal infection in the specimens obtained from mice was observed. IL-10 was also detected in the bloodstreams earlier than the peaks of TNF-alpha and IL-6 during lethal infection, while IL-4 was never detected in the sera. The administration of monoclonal antibodies (mAbs) against TNF-alpha, IFN-gamma, IL-6, IL-4 or IL-10 failed to rescue mice from lethal L. monocytogenes infection, whereas anti-TNF-alpha mAb and anti-IFN-gamma mAb prevented mice from lethality by high-dose endotoxin shock. These results suggest that lethality in L. monocytogenes infection might not be determined solely by these cytokines.

Various bacterial pathogens have been identified as mediators of apoptosis. Apoptosis reportedly shows both detrimental and beneficial effects on biological functions. We studied the role of liver apoptosis in lethal Listeria monocytogenes infection and the regulation of apoptosis by endogenous cytokines during infection. Apoptosis was observed in the spleen but not in the liver of infected mice, whereas the induction of liver necrosis was evident by rising levels of serum aminotransferases in these animals. Apoptosis was detected in the liver of L. monocytogenes-infected mice which had been treated with monoclonal antibody (mAb) against tumor necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6), or in TNF-alpha(-/-) mice, but not in gamma- interferon (IFN-gamma)(-/-) mice or mice which had been treated with mAb against IL-4 or IL-10. Augmentation of liver apoptosis in mice treated with mAb against TNF-alpha or IL-6 or in TNF-alpha(-/-) mice correlated with the increase in bacterial numbers in the organ, while no augmentation of apoptosis was observed in the liver of IFN-gamma(-/-) mice irrespective of the marked increase in bacterial numbers in the organs, indicating that augmentation of liver apoptosis may not be merely due to the increase in bacterial growth in the organs. These results suggest that TNF-alpha and IL-6 may play an important role in protecting the liver from apoptosis in lethal L. monocytogenes infection.