Critical Roles of Myeloid Differentiation Factor 88-Dependent Proinflammatory Cytokine Release in Early Phase Clearance of Listeria monocytogenes in Mice

• Published in: The Journal of immunology (1950) 2002-10, Vol.169 (7), p.3863-3868
• Main Authors: Seki, Ekihiro, Tsutsui, Hiroko, Tsuji, Noriko M, Hayashi, Nobuki, Adachi, Keishi, Nakano, Hiroki, Futatsugi-Yumikura, Shizue, Takeuchi, Osamu, Hoshino, Katsuaki, Akira, Shizuo, Fujimoto, Jiro, Nakanishi, Kenji
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Antigens, Differentiation - physiology; Cytokines - metabolism; Drosophila Proteins; Female; Immunity, Innate - genetics; Inflammation - genetics; Inflammation - immunology; Inflammation - microbiology; Interferon-gamma - biosynthesis; Interleukin-12 - deficiency; Interleukin-12 - genetics; Interleukin-12 - metabolism; Interleukin-12 - physiology; Interleukin-18 - deficiency; Interleukin-18 - genetics; Interleukin-18 - physiology; Listeria monocytogenes - growth & development; Listeria monocytogenes - immunology; Listeriosis - genetics; Listeriosis - immunology; Listeriosis - microbiology; Listeriosis - pathology; Liver - immunology; Liver - microbiology; Liver - pathology; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Neutrophil Infiltration - genetics; Neutrophil Infiltration - immunology; Receptors, Cell Surface - physiology; Receptors, Immunologic - physiology; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.169.7.3863

Listeria monocytogenes (LM), a facultative intracellular Gram-positive bacterium, often causes lethal infection of the host. In this study we investigated the molecular mechanism underlying LM eradication in the early phase of infection. Upon infection with LM, both IL-12 and IL-18 were produced, and then they synergistically induced IFN-gamma production, leading to normal LM clearance in the host. IFN-gamma knockout (KO) mice were highly susceptible to LM infection. IL-12/IL-18 double knockout mice were also highly susceptible. Their susceptibility was less than that of IFN-gamma KO mice, but more than that of single IL-12 or IL-18 KO mice. Mice deficient in myeloid differentiation factor 88 (MyD88), an essential adaptor molecule used by signal transduction pathways of all members of the Toll-like receptor (TLR) family, showed an inability to produce IL-12 and IFN-gamma following LM infection and were most susceptible to LM. Furthermore, MyD88-deficient, but not IFN-gamma-deficient, Kupffer cells could not produce TNF-alpha in response to LM in vitro, indicating the importance of MyD88-dependent TNF-alpha production for host defense. As TLR2 KO, but not TLR4 KO, mice showed partial impairment in their capacity to produce IL-12, IFN-gamma, and TNF-alpha, TLR2 activation partly contributed to the induction of IL-12-mediated IFN-gamma production. These results indicated a critical role for TLRs/MyD88-dependent IL-12/TNF-alpha production and for IL-12- and IL-18-mediated IFN-gamma production in early phase clearance of LM.