Endogenous
interleukin-12 (IL-12) mediates protection against Yersinia enterocolitica in C57BL/6 mice by triggering
gamma interferon (IFN-gamma) production in NK and CD4+ T cells. Administration of exogenous
IL-12 confers protection against yersiniae in Yersinia-susceptible BALB/c mice but exacerbates
yersiniosis in resistant C57BL/6 mice. Therefore, we wanted to dissect the different mechanisms exerted by
IL-12 during
Yersinia infections by using different models of Yersinia-resistant and -susceptible mice, including resistant C57BL/6 mice, susceptible BALB/c mice, intermediate-susceptible wild-type 129/Sv mice, 129/Sv IFN-gamma-receptor-deficient (IFN-gamma R-/-) mice and C57BL/6
tumor necrosis factor (
TNF) receptor p55 chain-deficient (TNFR p55-/-) mice. IFN-gamma R-/- mice turned out to be highly susceptible to
infection by Y. enterocolitica compared with IFN-gamma R+/+ mice. Administration of
IL-12 was protective in IFN-gamma R+/+ mice but not in IFN-gamma R-/- mice, suggesting that IFN-gamma R-induced mechanisms are essential for IL-12-induced resistance against yersiniae. BALB/c mice could be rendered Yersinia resistant by administration of anti-CD4
antibodies or by administration of
IL-12. In contrast, C57BL/6 mice could be rendered more resistant by administration of
transforming growth factor beta (
TGF-beta). Furthermore, IL-12-triggered toxic effects in C57BL/6 mice were abrogated by coadministration of
TGF-beta. While administration of
IL-12 alone increased
TNF-alpha levels, administration of
TGF-beta or
TGF-beta plus
IL-12 decreased both
TNF-alpha and IFN-gamma levels in Yersinia-infected C57BL/6 mice. Moreover,
IL-12 did not induce toxicity in Yersinia-infected TNFR p55-/- mice, suggesting that
TNF-alpha accounts for IL-12-induced toxicity. Taken together,
IL-12 may induce different effector mechanisms in BALB/c and C57BL/6 mice resulting either in protection or exacerbation. These results are important for understanding the critical balance of proinflammatory and regulatory
cytokines in
bacterial infections which is decisive for beneficial effects of
cytokine therapy.