Inhibition of interferon-gamma-mediated activation in mouse macrophages treated with lipoarabinomannan

Lipoarabinomannan (LAM), purified from the cell walls of Mycobacterium leprae and M. tuberculosis, is a potent inhibitor of interferon-gamma (IFN-γ) mediated activation of macrophages. The capability of LAM to inhibit IFN-γ activation of macrophages in vitro was dose dependent and required a 24-h pre-exposure. Defective activation was evident as a block in IFN-γ-induced cytocidal activity for tumour cell targets and microbicidal capacity for intracellular Toxoplasma gondii. Additionally, LAM treatment blocked the induction of surface Ia antigens on peritoneal macrophages by IFN-γ. The requirement for pretreatment with LAM was further substantiated by the finding that peritoneal macrophages that were activated in vivo were not affected by LAM treatments and retained full microbicidal function. However, once inhibited by LAM treatment in vitro, macrophages remained fully refractory to IFN-γ activation for up to 5 days in culture. Inhibition of IFN-γ activation in macrophages treated with LAM was not overcome by 100-fold increases in the dose of IFN-γ used or by a constant dose of IFN-γ in combination with 100-fold increases in the level of endotoxin used to trigger cytotoxic activity. The defect in IFN-γ unresponsiveness was not due to altered receptor function, as control and LAM-treated macrophages showed similar capacity to bind, internalize, and digest radiolabelled IFN-γ. Based on the in vitro findings reported here, the inhibition of IFN-γ-mediated macrophage activation by exposure to LAM may contribute to defective macrophage function observed in lepromatous granulomas and thus constitutes an important aspect of pathogenesis in mycobacterioses.