Macrophages are a significant source of type 1 cytokines during mycobacterial infection

J Clin Invest. 1999 Apr;103(7):1023-9. doi: 10.1172/JCI6224.

Abstract

T-helper 1 (Th1) cells are believed to be the major producer of the type 1 cytokine interferon-gamma (IFN-gamma) in cell-mediated immunity against intracellular infection. We have investigated the ability of macrophages to release type 1 cytokines and their regulatory mechanisms using both in vivo and in vitro models of pulmonary mycobacterial infection. During pulmonary infection by live Mycobacterium bovis bacilli Calmette-Guérin (BCG) in wild-type mice, lung macrophages released interleukin-12 (IL-12), IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha), and expressed surface activation markers. However, macrophages in infected IL-12(-/-) mice released TNF-alpha but not IFN-gamma and lacked surface activation makers. In freshly isolated lung macrophages from naive IL-2(-/-) mice, mycobacteria alone released TNF-alpha but not IFN-gamma, whereas exogenously added IL-12 alone released a minimum of IFN-gamma. However, these macrophages released large quantities of IFN-gamma upon stimulation with both mycobacteria and IL-12. In contrast, mycobacteria and exogenous IFN-gamma released only a minimum of endogenous IFN-gamma. Endogenous IL-18 (IFN-gamma-inducing factor) played little role in IFN-gamma responses by macrophages stimulated by mycobacteria and IL-12. Our data reveal that macrophages are a significant source of type 1 cytokines during mycobacterial infection and that both IL-12 and intracellular pathogens are required for the release of IFN-gamma but not TNF-alpha. These findings suggest that macrophages regulate cell-mediated immunity by releasing not only IL-12 and TNF-alpha but also IFN-gamma and that full activation of IFN-gamma response in macrophages is tightly regulated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism*
  • Flow Cytometry
  • Interferon-gamma / pharmacology
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism
  • Interleukins / metabolism
  • Lung / microbiology*
  • Macrophages / metabolism*
  • Mice
  • Mice, Knockout
  • Mycobacterium Infections / metabolism*
  • Mycobacterium Infections / microbiology
  • Mycobacterium bovis / metabolism*
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Cytokines
  • Interleukins
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma