Essential role for the p40 subunit of interleukin-12 in neutrophil-mediated early host defense against pulmonary infection with Streptococcus pneumoniae: involvement of interferon-gamma.
Interleukin (IL)-12 is a critical cytokine in the T helper (Th)1 response and host defense against intracellular microorganisms, while its role in host resistance to extracellular bacteria remains elusive. In the present study, we elucidated the role of IL-12 in the early-phase host defense against acute pulmonary infection with Streptococcus pneumoniae, a typical extracellular bacterium, using IL-12p40 gene-disrupted (IL-12p40KO) mice. IL-12p40KO mice were highly susceptible to S. pneumoniae infection, as indicated by the shortened survival time, which was completely restored by the replacement therapy with recombinant (r) IL-12, and increased bacterial counts in the lung. In these mice, recruitment of neutrophils in the lung was significantly attenuated when compared to that in wild-type (WT) mice, which correlated well with the reduced production of macrophage inflammatory protein (MIP-2) and tumor necrosis factor (TNF)-alpha in the infected tissues at the early phase of infection. In vitro synthesis of both cytokines by S. pneumoniae-stimulated lung leukocytes was significantly lower in IL-12p40KO mice than in WT mice, and addition of rIL-12 or interferon (IFN)-gamma restored the reduced production of MIP-2 and TNF-alpha in IL-12p40KO mice. Neutralizing anti-IFN-gamma monoclonal antibody (mAb) significantly decreased the effect of rIL-12. Anti-IFN-gamma mAb shortened the survival time of infected mice and reduced the recruitment of neutrophils and production of MIP-2 and TNF-alpha in the lungs. Our results indicated that IL-12p40 plays a critical role in the early-phase host defense against S. pneumoniae infection by promoting the recruitment of neutrophils to the infected tissues.
Yamamoto
Natsuo
N
Division of Infectious Diseases, Department of Internal Medicine, Graduate School and Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. summer-m@mx2.nisiq.net
Kawakami
Kazuyoshi
K
Kinjo
Yuki
Y
Miyagi
Kazuya
K
Kinjo
Takeshi
T
Uezu
Kaori
K
Nakasone
Chikara
C
Nakamatsu
Masashi
M
Saito
Atsushi
A
D000818:Animals; D054426:Chemokine CXCL2; D007371:Interferon-gamma / Q000032:analysis / Q000502:physiology*; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D015846:Monokines / Q000032:analysis / Q000502:physiology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D011018:Pneumonia, Pneumococcal / Q000276:immunology*; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000502:physiology
D054426:Chemokine CXCL2; D015846:Monokines; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma