Essential role for the p40 subunit of interleukin-12 in neutrophil-mediated early host defense against pulmonary infection with Streptococcus pneumoniae: Involvement of interferon-γ

Natsuo Yamamoto, Kazuyoshi Kawakami, Yuki Kinjo, Kazuya Miyagi, Takeshi Kinjo, Kaori Uezu, Chikara Nakasone, Masashi Nakamatsu, Atsushi Saito

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

Abstract

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)-α 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)-γ restored the reduced production of MIP-2 and TNF-α in IL-12p40KO mice. Neutralizing anti-IFN-γ monoclonal antibody (mAb) significantly decreased the effect of rIL-12. Anti-IFN-γ mAb shortened the survival time of infected mice and reduced the recruitment of neutrophils and production of MIP-2 and TNF-α 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.

Original languageEnglish
Pages (from-to)1241-1249
Number of pages9
JournalMicrobes and Infection
Volume6
Issue number14
DOIs
Publication statusPublished - 2004 Nov
Externally publishedYes

Keywords

  • IL-12
  • MIP-2
  • Neutrophils
  • Pneumococcal infection
  • TNF-α

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Infectious Diseases

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