TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-12 CONTRIBUTE TO RESISTANCE TO THE INTRACELLULAR BACTERIUM BRUCELLA-ABORTUS BY DIFFERENT MECHANISMS

Both interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha ) are produced early in intracellular bacterial infection. Depletion o f either IL-12 or TNF-alpha by a single injection of specific antibody 4 h before the injection of Brucella abortus 19 led to the exacerbati on of infection w,eeks later. Whereas the effect of IL-12 depletion on resistance was persistent and exacerbation was still significant 6 we eks later, the bacterial numbers in mice depleted of TNF-alpha were si milar to the bacterial numbers in control infected mice by 6 weeks pos tinfection. Massive splenomegaly, which is often seen in 2-week Brucel la-infected mice, was not observed in IL-12- or TNF-alpha-depleted mic e. Both IL-12- and TNF-alpha-depleted mice showed reduced cell accumul ation in the spleen compared with the massive cell accumulation in con trol infected mice. Granuloma formation in livers was much reduced in IL-12-depleted mice but not in TNF-alpha-depleted mice. Gamma interfer on (IFN-gamma) production by cells from TNF-alpha-depleted mice was no t significantly different from that of cells from control infected mic e. In contrast, the production of IFN-gamma by both CD4(+) and CD8(+) T cells from IL-12-depleted mice was greatly reduced, compared with th at from control infected mice. This effect was still observed when the antibody injection was delayed for up to 7 days postinfection, but in jections of anti-IL-12 antibody into mice with established Brucella in fection had no significant effect on IFN-gamma production by T cells. Taken together, these results suggested that IL-12 contributed to resi stance mainly via an IFN-gamma-dependent pathway and had a profound ef fect on the induction of acquired cellular resistance. In contrast, TN F-alpha. was involved in resistance possibly via direct action on effe ctor cells and may not be essential for the induction of acquired cell ular resistance.