Retrovirus‐elicited interleukin‐12 and tumour necrosis factor‐α as inducers of interferon‐γ‐mediated pathology in mouse AIDS

Publisher Website
Google Scholar
Abstract
Spleen cells from mice resistant or sensitive to mouse acquired immune deficiency syndrome (MAIDS) were examined for cytokine mRNA. In MAIDS‐resistant BALB/c mice, cytokine transcripts peaked at 1 week after infection with Type 1 cytokines [interleukin‐2 (IL‐2), tumour necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ), IL‐12], dominating over Type 2 cytokines (IL‐4, IL‐10). Expression of cytokines other than IL‐2 later declined to levels seen in uninfected mice. In MAIDS‐sensitive B6 mice, transcripts for all cytokines were increased at 1 week and, except for IL‐2, increased progressively. Spontaneous production of IFN‐γ protein was associated with enhanced mRNA expression at 1 week after infection of either strain, but none was detectable in association with even higher levels of transcripts at later times after infection of B6 mice. Spleen cells from longer‐term‐infected B6 mice, however, produced substantial amounts of IFN‐γ following treatment with lipopolysaccharide (LPS) or IL‐12. Inclusion of anti‐IL‐12 or anti‐TNF‐α antibodies blocked induction of IFN‐γ by LPS. Induction of IFN‐γ by IL‐12 was potentiated by TNF‐α following stimulation of intact spleen cells and purified CD4+ or CD8+ T cells, as well as negatively selected CD4−8− cells from infected B6 mice. Further studies showed that IFN‐γ knockout mice on a B6 background developed MAIDS with a prolonged time–course, whereas BALB/c knockout mice were unchanged in their resistance to MAIDS. These studies suggest that continuing low‐level expression of IFN‐γ, stimulated by IL‐12 and TNF‐α, contributes to the susceptibility of B6 mice to MAIDS but is not required for the resistance of BALB/c mice to disease.