Enhancement of antimicrobial effects by glucocorticoids

In the past few years a body of evidence has accumulated showing that stimulation of human astrocytes and microvascular endothelial cells with IFN-gamma induces a potent antibacterial and anti-parasitic effect. We have found that the IFN-gamma-mediated activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) is, at least in part, responsible for this antimicrobial activity. Glucocorticoids are frequently used in inflammatory central nervous system diseases to reduce the inflammatory reaction and cerebral edema. Since in many inflammatory conditions infection is either a primary or secondary factor, steroids are administered, in these circumstances, during infection. We investigated whether steroids could affect the antimicrobial effect of IFN-gamma-induced IDO activation. We found that hydrocortisone and dexamethasone enhance IFN-gamma-mediated IDO activity in both human astrocytoma cells and native human astrocytes. Furthermore, we found that the amounts of IDO mRNA and of IDO protein are enhanced in cells treated with IFN-gamma and glucocorticoids. In addition, we were able to demonstrate that both steroids enhance the IFN-gamma-mediated antimicrobial activity against Toxoplasma gondii, Staphylococcus aureus and group B streptococci. The enhanced antimicrobial effect of IFN-gamma in the presence of glucocorticoids is due to the enhancement of the IDO-mediated tryptophan degradation, demonstrated by the complete abrogation of this antimicrobial effect by tryptophan resupplementation. These data show that glucocorticoids, which were often used to inhibit proinflammatory processes, do not decrease IDO-mediated antimicrobial effects. In contrast, high doses of steroids were able to enhance the IFN-gamma-induced antimicrobial activity.