Regulation of IDO-mediated bacteriostasis in macrophages: role of antibiotics and anti-inflammatory agents.
Induction of IDO is also under strict control by the immune system and we have previously shown that there are a number of cytokines involved in the down-regulation of IDO induction. In clinical practice anti-inflammatory substances and antibiotics are commonly used and may influence the outcome of bacterial infection. We analysed the IFNgamma-dependant IDO induction and bacteriostasis of Staphylococcus aureus and Group A Streptococcus (GAS) in monocyte-derived-macrophages (MDM) from cord blood and peripheral blood of healthy adult donors with attention to the effect of down-regulatory cytokines and of two commonly used anti-inflammatory agents, hydrocortisone and indomethacin, on both IDO activity and bacterial growth. In addition to this we were interested in the effect of sub-inhibitory concentrations of the antibiotic ampicillin on this IDO-mediated effect, the premise being that for a substantial period of antibiotic therapy the infection site is exposed to sub-inhibitory concentrations of antibiotic. We found that after stimulation with IFNgamma, MDM inhibited streptococcal growth. This was due to IFNgamma-induced IDO activity as demonstrated by reconstitution of growth by supplemental tryptophan. This IDO-mediated bacteriostasis was inhibited by the cytokines IL-10, IL-4 and TGFbeta. Furthermore, addition of indomethacin to IFNgamma stimulated MDM also resulted in the abrogation of the IDO-induced bacteriostasis, a result of the inhibition of IDO induction. Surprisingly, co-stimulation with hydrocortisone and IFNgamma apparently increased the IDO activity in cord blood MDM, but had no effect on the IDO-activity of adult peripheral blood MDM. Bacteriostasis in cord blood MDM, on the other hand, was not affected by co-stimulation with hydrocortisone. Ampicillin, in sub-inhibitory concentrations had no effect on the IDO activity itself but did have a synergistic effect on the IDO-induced bacteriostasis in MDM cultures. We conclude that therapy with indomethacin may increase the risk of clinically important bacterial infection due to the inhibition of the IDO-induced bacteriostasis. In addition sub-inhibitory concentrations of ampicillin may play a role in the area of infection where IFNgamma stimulated macrophages are to be found in abundance.
MacKenzie
Colin R
CR
Institute of Medical Microbiology and Virology, Heinrich-Heine-University, Moorenstr. 5, D-40225 Duesseldorf, Germany. colin.mackenzie@uni-duesseldorf.de
Worku
Daniel
D
Däubener
Walter
W
D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007213:Indomethacin / Q000494:pharmacology; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology*; D011994:Recombinant Proteins; D013211:Staphylococcus aureus / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D014366:Tryptophan Oxygenase / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011994:Recombinant Proteins; D000667:Ampicillin; D007371:Interferon-gamma; D014366:Tryptophan Oxygenase; D006854:Hydrocortisone; D007213:Indomethacin