RETROVIRUS-ELICITED INTERLEUKIN-12 AND TUMOR-NECROSIS-FACTOR-ALPHA ASINDUCERS OF INTERFERON-GAMMA-MEDIATED PATHOLOGY IN MOUSE AIDS

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 in fection with Type 1 cytokines [interleukin-2 (IL-2), tumour necrosis f actor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-12], dominat ing 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 w eek and, except for IL-2, increased progressively. Spontaneous product ion of IFN-gamma 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 aft er infection of B6 mice. Spleen cells from longer-term-infected B6 mic e, however, produced substantial amounts of IFN-gamma following treatm ent with lipopolysaccharide (LPS) or IL-12. Inclusion of anti-IL-12 or anti-TNF-alpha antibodies blocked induction of IFN-gamma by LPS. Indu ction of IFN-gamma by IL-12 was potentiated by TNF-alpha following sti mulation 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-gamma knockout mice on a B6 backgrou nd developed MAIDS with a prolonged time-course, whereas BALB/c knocko ut mice were unchanged in their resistance to MAIDS. These studies sug gest that continuing low-level expression of IFN-gamma, stimulated by IL-12 and TNF-alpha, contributes to the susceptibility of B6 mice to M AIDS but is not required for the resistance of BALB/c mice to disease.