IFN-alpha beta-dependent, IFN-gamma secretion by bone marrow-derived macrophages controls an intracellular bacterial infection.
Several reports have indicated that cell lineages apart from NK and T cells can also express IFN-gamma. However, the biological relevance of this finding is uncertain. We show in this study that bone marrow-derived macrophages (BMMs) express IFN-gamma at the mRNA and protein level early after infection with Chlamydia pneumoniae. Increased IFN-gamma mRNA accumulation by infected BMMs is early, transient, and requires both bacterial and host protein synthesis. The induction of IFN-gamma mRNA levels is independent of IL-12 and was dramatically enhanced in IL-10(-/-) BMMs. Such IL-10(-/-) BMMs contained less bacteria than the wild-type controls, whereas IFN-gammaR(-/-) BMMs showed increased C. pneumoniae load. Inducible NO synthase (iNOS) also participates in the control of bacterial load, as shown by the enhanced numbers of C. pneumoniae in iNOS(-/-) BMMs. However, the increased accumulation of iNOS mRNA and NO in C. pneumoniae-infected BMMs depended on the presence of IFN-alphabeta, but was independent of IFN-gamma. Interestingly, IFN-alphabeta are also required for increased IFN-gamma mRNA accumulation in C. pneumoniae-infected BMMs. Accordingly, IFN-alphabetaR(-/-) BMMs showed higher levels of C. pneumoniae than wild-type BMMs. Our findings unravel an autocrine/paracrine macrophage activation pathway by showing an IFN-alphabeta-dependent IFN-gamma and iNOS induction in response to infection, which protects macrophages against intracellular bacterial growth.
Rothfuchs
A G
AG
Microbiology and Tumorbiology Center, Astrid Lindgren's Hospital, Karolinska Institutet, Stockholm, Sweden.
Gigliotti
D
D
Palmblad
K
K
Andersson
U
U
Wigzell
H
H
Rottenberg
M E
ME
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D002478:Cells, Cultured; D016993:Chlamydophila pneumoniae / Q000254:growth & development* / Q000276:immunology*; D006131:Growth Inhibitors / Q000378:metabolism / Q000502:physiology; D007370:Interferon Type I / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D000900:Anti-Bacterial Agents; D006131:Growth Inhibitors; D007370:Interferon Type I; D012333:RNA, Messenger; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse