Distinct functions of interferon-gamma for chemokine expression in models of acute lung inflammation

Challenge of the immune system with bacterial superantigens or endotoxin in duces the systemic release of cytokines followed by lethal septic shock. Th e lung is particularly susceptible to systemic toxin exposure resulting in acute leucocyte infiltration and vascular damage. In the present study, the functions of interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) for chemokine regulation during acute lung inflammation were examined. Fol lowing administration of the superantigen, staphylococcal enterotoxin B (SE B), lung mRNA levels of the chemokines cytokine-induced neutrophil chemo-at tractant (KC), lipopolysaccharide-induced CXC chemokine (LIX), macrophage c hemotactic protein-1 (MCP-I), macrophage inflammatory protein (MIP)-1 alpha and MIP-2 were increased to a similar extent both in controls and in mice deficient for the IFN-gamma or 55 000 MW TNF receptors. In contrast, interf eron-inducible protein-10 (IP-10) and monokine induced by IFN-gamma (Mig) m RNA expression was markedly reduced in mice deficient for IFN-gamma or IFN- gamma receptor, but not in 55000 MW TNF receptor knockout mice. in situ hyb ridization experiments demonstrated that IP-10 was highly expressed in lung interstitial macrophages of C57BL/6, but not of IFN-gamma receptor-deficie nt mice. In contrast to SEE administration, treatment with lipopolysacchari de resulted in a strong induction of IP-IO and Mig in IFN-gamma receptor-de ficient mice. Together, these results establish a critical function of IFN- gamma for chemokine induction in acute lung inflammation that is dependent on the nature of the inflammatory stimulus.