Interleukin 18 contributes to host resistance and gamma interferon production in mice infected with virulent Salmonella typhimurium

Spleen and peritoneal macrophages obtained from innately resistant A/J mice released low levels of interleukin 18 (IL-18) upon infection with Salmonel la typhimurium C5 RP4. Incubating the cells with recombinant gamma interfer on (rIFN-gamma) enhanced IL-18 production. A/J mice treated in vivo with an ti-IL-18 antibodies showed impaired resistance to infection, with increased bacterial loads in the liver and spleen. Administration of rIL-18 could pr otect A/J mice from challenge with a lethal dose of virulent salmonellae, w ith a dramatic reduction in bacterial numbers in the tissues. rIL-18 admini stration did not ameliorate the disease in IFN-gamma-R-/- mice. IL-18 prove d to be required for IFN-gamma production by mouse splenocytes from convent ional, scid, and rag-1(-/-) mice;in vivo IL-18 neutralization caused a decr ease in circulating IFN-gamma levels. Thus, IL-18 is a key factor in early host resistance to Salmonella and probably acts via IFN-gamma.