and nitric oxide from macrophages via IFN-
induction
Department of Pathology and Molecular Medicine, and Division of Infectious Diseases, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada
Correspondence: Dr. Zhou Xing, Rm. 4H19, Health Science Centre, Department of Pathology and Molecular Medicine, McMaster University, 1200 Main St. West, Hamilton, Ontario L8N 3Z5, Canada. E-mail: xingz{at}fhs.mcmaster.ca
IL-12 is believed to play an important role in cell-mediated immunity
against intracellular infection primarily by acting on T and NK cells.
Recent evidence has suggested, however, that IL-12 has broader cellular
targets than previously thought. In this study, we examined the role of
IL-12 in macrophage TNF-
and nitric oxide (NO) release by using an
in vitro model of intracellular infection. IL-12 alone
released relatively little TNF- and NO, whereas live mycobacteria
alone released TNF- markedly but little NO from murine alveolar
macrophages. However, IL-12 and mycobacteria together enhanced TNF-
and NO release synergistically. Because IL-12 and mycobacteria also
released IFN-
from macrophages synergistically, and exogenous
IFN- with mycobacteria enhanced TNF- and NO release
synergistically, we examined the role of endogenous IFN- in
IL-12/mycobacteria-stimulated macrophage activation. Using macrophages
from mice deficient in IFN-, we found that
IL-12/mycobacteria-enhanced macrophage TNF- and NO release was
mediated through endogenous IFN-. We further demonstrated that
IFN- and mycobacteria together had a selective effect on macrophage
cytokine release because they released TNF- synergistically but not
macrophage chemotactic protein-1 (MCP-1). These findings reveal that
IL-12 can activate macrophages potently during intracellular infection,
and this activating effect is mediated primarily through its effect on
macrophage IFN- release.
Key Words: nitric oxide • MCP-1 • cytokine • tuberculosis
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