INTERLEUKIN-12 IS REQUIRED FOR CONTROL OF THE GROWTH OF ATTENUATED AROMATIC-COMPOUND-DEPENDENT SALMONELLAE IN BALB C MICE - ROLE OF GAMMA-INTERFERON AND MACROPHAGE ACTIVATION/

The attenuated S. typhimurium SL3261 (aroA) strain causes mild infecti ons in BALB/c mice. We were able to exacerbate the disease by administ ering anti-interleukin-12 (IL-12) antibodies, resulting in bacterial c ounts in the spleens and livers of anti-IL-12-treated mice that were 1 0- to 100-fold higher than the ones normally observed in premortem mic e; yet the animals showed only mild signs of illness. Nevertheless, th ey eventually died of a slow, progressive disease. Mice infected with salmonellae become hypersusceptible to endotoxin, We found that IL-12 neutralization prevented the death of infected mice following subcutan eous injection of lipopolysaccharide. Granulomatous lesions developed in the spleens and livers of control animals, as opposed to a widespre ad infiltration of mononuclear cells seen in the organs of anti-IL-12- treated mice. In the latter (heavily infected), salmonellae were seen within mononuclear cells, indicating an impairment of the bactericidal or bacteriostatic ability of the phagocytes in the absence of biologi cally active IL-12, Gamma interferon (IFN-gamma) levels were reduced i n the sera and tissue homogenates from anti-IL-12-treated mice compare d to those in control animals. Furthermore, fluorescence-activated cel l sorter analysis on spleen cells shelved that IL-12 neutralization im paired the upregulation of I-A(d)/I-E-d antigens on macrophages from i nfected mice. Inducible nitric oxide synthase and IFN-gamma mRNA produ ction was down-regulated in anti-IL-12-treated mice, which also showed an increased production of IL-10 mRNA and a decrease in nitric oxide synthase activity in the tissues. Administration of recombinant IFN-ga mma to anti-IL-12-treated mice was able to restore host resistance, gr anuloma formation, and expression of major histocompatibility complex class II antigens in F4/80(+) and CD11b(+) spleen cells.