Chronic administration of dexamethasone results in Fc receptor up-regulation and inhibition of class I antigen expression on macrophages from MRL/lpr autoimmune mice.
The MRL/lpr mouse develops, after approximately 8 weeks of age, a severe autoimmune syndrome with many features resembling human systemic lupus erythematosus, including autoantibodies against DNA and basement membranes resulting in immune complexes, vasculitis, and multiorgan disease. While this murine model of lupus has been used for the identification of therapeutics with potential efficacy in human autoimmune disease, the long-term impact of chronic immunosuppressive therapy on macrophage function in this paradigm is not understood. To this end, MRL/lpr mice were treated prophylactically with dexamethasone at 0.01, 0.1, and 1 mg/kg of body weight for 20 weeks or were allowed to develop autoimmune disease and, at 15 weeks of age, treated therapeutically with 1-mg/kg dexamethasone for 8 additional weeks. Analysis of surface antigens on resident peritoneal macrophages demonstrated a progressive loss in class I expression with a concomitant increase in Fc receptor expression. Neither phagocytosis nor CD11b expression was modulated with chronic steroid treatment. Furthermore, dexamethasone treatment was associated with a reduction in anti-DNA antibodies and total immunoglobulin G and yet an elevation in serum cholesterol due to an increase in high-density lipoproteins. Therefore, the MRL/lpr mouse serves not only as a small-animal model of autoimmune disease but also as one in which the negative and positive sequelae associated with chronic immunosuppression can be further understood.
Zuckerman
S H
SH
Division of Cardiovascular Research, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA.
Evans
G F
GF
Bryan
N
N
D000818:Animals; D015415:Biomarkers / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000187:drug effects* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011961:Receptors, Fc / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D015415:Biomarkers; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D011961:Receptors, Fc; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone