Dexamethasone blocks the interferon-gamma-mediated downregulation of the macrophage mannose receptor.
The macrophage mannose receptor is highly susceptible to modulation by a variety of proinflammatory and antiinflammatory agents. Previous studies have demonstrated that mannose receptor activity is dramatically increased in rat bone marrow-derived macrophages by dexamethasone treatment and decreased following incubation with interferon-gamma (IFN-gamma). Regulation by both agents occurs at least in part by alteration of mannose receptor mRNA levels. In the present study, we have investigated the ability of dexamethasone to block mannose receptor downregulation in rat marrow macrophages by IFN-gamma. Incubation of rat macrophages with IFN-gamma resulted in downregulation of mannose receptor activity, receptor synthesis, and mRNA levels, with no change in turnover rate of the receptor. IFN-gamma appeared to act at least partially through the generation of nitric oxide: inclusion of the nitric oxide inhibitor N-monomethyl arginine inhibited the IFN-gamma-induced effects on the mannose receptor by approximately 50%. When cells were coincubated with dexamethasone plus IFN-gamma, dexamethasone blocked the decrease in mannose receptor activity, synthesis, and mRNA. Additionally, dexamethasone inhibited nitric oxide production in response to IFN-gamma. These results suggest that mannose receptor expression is downregulated by IFN-gamma by at least two mechanisms: a decrease in mannose receptor mRNA levels and inhibition involving the production of nitric oxide. Dexamethasone has the capability of blocking the effect of IFN-gamma on mannose receptor expression through inhibition of IFN-gamma-mediated downregulation of mannose receptor transcription and/or inhibition of IFN-gamma-mediated induction of nitric oxide production.
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
V L
VL
Shepherd
H B
HB
Cowan
R
R
Abdolrasulnia
S
S
Vick
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001854:Bone Marrow Cells; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006735:Horseradish Peroxidase / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D037181:Lectins, C-Type; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D019323:omega-N-Methylarginine
D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D003907:Dexamethasone; D007371:Interferon-gamma; D001120:Arginine; D006735:Horseradish Peroxidase