BACKGROUND: Interferons play a critical role in regulating both the innate and adaptive immune responses. Previous reports have shown increased levels of IFN-gamma, IFN-gamma-inducing IL-12 and IFN-gamma-inducible chemokine IP-10 in patients with chronic obstructive pulmonary disease (COPD). METHODS: The present study focuses on the regulation of the IP-10 secretion in co-cultures of lung epithelial cells and peripheral blood mononuclear cells (PBMCs). RESULTS: No IP-10 secretion was detected in cells cultured alone, whereas a significant increase in IP-10 levels was observed in epithelial cell/PBMC co-cultures. Furthermore, the results show that interactions between lung epithelial cells, lymphocytes and monocytes are needed for basal IP-10 secretion. Interestingly, we have also shown that incubation with IL-12 can induce an IFN-gamma independent increase in IP-10 levels in co-cultures. Furthermore, inhibition studies supported the suggestion that different intracellular pathways are responsible of IFN-gamma and IL-12 mediated IP-10 secretion. CONCLUSION: These studies demonstrate a novel diversity in IFN-gamma/IL-12 pathways, showing that the IP-10 expression in co-cultures is regulated by multiple factors, such as intercellular interactions in addition to IFN-gamma and IL-12 levels. These results may be valuable in designing novel strategies to antagonize IP-10 mediated immunological reactions and chemotactic effects on T cells.