TY - JOUR
T1 - Interferon-γ production and host protective response against Mycobacterium tuberculosis in mice lacking both IL-12p40 and IL-18
AU - Kawakami, Kazuyoshi
AU - Kinjo, Yuki
AU - Uezu, Kaori
AU - Miyagi, Kazuya
AU - Kinjo, Takeshi
AU - Yara, Satomi
AU - Koguchi, Yoshinobu
AU - Miyazato, Akiko
AU - Shibuya, Kazutoshi
AU - Iwakura, Yoichiro
AU - Takeda, Kiyoshi
AU - Akira, Shizuo
AU - Saito, Atsushi
N1 - Funding Information:
This work was supported in part by Grants from the Ministry of Health and Welfare, Japan.
PY - 2004/4
Y1 - 2004/4
N2 - Interferon (IFN)-γ plays an essential role in host defense against infection with Mycobacterium tuberculosis, and its synthesis is critically regulated by interleukin (IL)-12, IL-18 and the recently identified IL-23. The present study was designed to determine the roles of these cytokines in IFN-γ-mediated host defenses against M. tuberculosis. For this purpose, we compared host protective responses in IL-12p40 and IL-18 double-knockout (DKO) mice (which lacked both IL-12/IL-18 and also IL-23) and IFN-γ gene-disrupted (GKO) mice. DKO mice were more resistant to the infection than GKO mice, as indicated by their extended survival and reduced live colony numbers in spleen, liver and lung. IFN-γ was detected by ELISA in liver and lung homogenates, but not in spleen and serum, and in all organs by RT-PCR in DKO mice at comparable or reduced levels to those in wild-type mice. IFN-γ production was reduced by depletion of CD4+ T cells, but not of natural killer (NK), NKT, γδT and dendritic cells. Neutralization of IFN-γ or TNF-α by specific monoclonal antibodies (mAbs) significantly shortened the survival time of the infected DKO mice. Furthermore, anti-TNF-α mAb partially attenuated IFN-γ synthesis in the liver of these mice. Finally, the expression level of inducible nitric oxide synthase (iNOS) mRNA in the spleen, liver and lung was considerable in DKO mice but only marginal or undetected in GKO mice. Our results indicate the presence of IL-12-, IL-18- and IL-23-independent host protective responses against mycobacterial infection mediated by IFN-γ, which was secreted from helper T cells.
AB - Interferon (IFN)-γ plays an essential role in host defense against infection with Mycobacterium tuberculosis, and its synthesis is critically regulated by interleukin (IL)-12, IL-18 and the recently identified IL-23. The present study was designed to determine the roles of these cytokines in IFN-γ-mediated host defenses against M. tuberculosis. For this purpose, we compared host protective responses in IL-12p40 and IL-18 double-knockout (DKO) mice (which lacked both IL-12/IL-18 and also IL-23) and IFN-γ gene-disrupted (GKO) mice. DKO mice were more resistant to the infection than GKO mice, as indicated by their extended survival and reduced live colony numbers in spleen, liver and lung. IFN-γ was detected by ELISA in liver and lung homogenates, but not in spleen and serum, and in all organs by RT-PCR in DKO mice at comparable or reduced levels to those in wild-type mice. IFN-γ production was reduced by depletion of CD4+ T cells, but not of natural killer (NK), NKT, γδT and dendritic cells. Neutralization of IFN-γ or TNF-α by specific monoclonal antibodies (mAbs) significantly shortened the survival time of the infected DKO mice. Furthermore, anti-TNF-α mAb partially attenuated IFN-γ synthesis in the liver of these mice. Finally, the expression level of inducible nitric oxide synthase (iNOS) mRNA in the spleen, liver and lung was considerable in DKO mice but only marginal or undetected in GKO mice. Our results indicate the presence of IL-12-, IL-18- and IL-23-independent host protective responses against mycobacterial infection mediated by IFN-γ, which was secreted from helper T cells.
KW - Host defense
KW - IFN-γ
KW - IL-12
KW - IL-18
KW - Mycobacterium tuberculosis
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U2 - 10.1016/j.micinf.2004.01.003
DO - 10.1016/j.micinf.2004.01.003
M3 - Article
C2 - 15050961
AN - SCOPUS:12144287655
VL - 6
SP - 339
EP - 349
JO - Microbes and Infection
JF - Microbes and Infection
SN - 1286-4579
IS - 4
ER -