title: Dexamethasone increases ROS production and T cell suppressive capacity by anti-inflammatory macrophages.
abstract: Macrophages have been demonstrated to suppress T cell responses by producing reactive oxygen species (ROS) leading to the subsequent induction of T regulatory cells in a ROS-dependent manner. Macrophages may therefore be instrumental in downregulating T cell responses in situations of exacerbated immune responses. Here we investigated the effect of immunosuppressive drugs on ROS production by macrophage subsets and the subsequent effects on T cell activation. Macrophage types 1 and 2 were differentiated with GM-CSF or M-CSF, in presence or absence of dexamethasone, cyclosporine A, FK506, rapamycin, or mycophenolic acid. The ROS producing capacity of fully differentiated Mph was highest in anti-inflammatory Mph2 and not affected by exposure to immunosuppressive drugs. However, presence of rapamycin during Mph2 differentiation decreased the ROS production of these cells. In contrast, other immunosuppressive drugs, with dexamethasone being the most potent, increased the ROS producing capacity of Mph2. Intriguingly although the ROS producing ability of Mph1 was unaffected, dexamethasone strongly increased the ROS producing capabilities of dendritic cells. Both at the mRNA and protein level we found that dexamethasone enhanced the expression of NOX2 protein p47(phox). Functionally, dexamethasone further enhanced the capacity of Mph2 to suppress T cell mediated IFN-γ and IL-4 production. In vivo, only in rats with normal ROS production (congenic DA.Ncf1(E3/E3)) it was observed that dexamethasone injection resulted in long-lasting upregulation of ROS production by macrophages and induced higher levels of Treg in a ROS-dependent manner. In conclusion, we show that the anti-inflammatory drug dexamethasone increases the ROS producing capacity of macrophages.
authors: Leiden University Medical Center, Department of Nephrology, 2300 RC Leiden, The Netherlands.
authors: Marina D
authors: MD
authors: Kraaij
authors: Sandra W
authors: SW
authors: van der Kooij
authors: Marlies E J
authors: ME
authors: Reinders
authors: Karin
authors: K
authors: Koekkoek
authors: Ton J
authors: TJ
authors: Rabelink
authors: Cees
authors: C
authors: van Kooten
authors: Kyra A
authors: KA
authors: Gelderman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D019255:NADPH Oxidases / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017382:Reactive Oxygen Species; D003907:Dexamethasone; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1