The dietary supplement ephedrine induces beta-adrenergic mediated exacerbation of systemic lupus erythematosus in NZM391 mice

The dietary supplement and adrenergic receptor agonist ephedrine has been a controversial topic as its safety has been questioned. Beta-adrenergic receptor (beta-AR) activation causes immunomodulation, which may contribute to promotion of autoimmune pathology. This report investigated the ability of ephedrine to exacerbate processes associated with autoimmune disease in a lupus-prone mouse model. To mimic human supplementation, ephedrine was administered to NZM391 (lupus-prone) and BALB/c (nonlupus prone) mice orally twice a day for three months at a dose of 50 and 100 microg/day. Some ephedrine-treated NZM391 mice also were preadministered the beta-AR antagonist propranolol to investigate beta-AR involvement. Mice were bled monthly, and sera were assayed for a variety of lupus manifestations and immunological measurements. In NZM391 males and females, both doses of ephedrine significantly increased lupus manifestations, including IgG production and organ-directed autoantibody titers, and significantly lowered the ratio of IgG2a/IgG1 compared to controls. Ephedrine significantly decreased female lifespan and significantly increased circulating populations of plasma cells (CD38(hi) CD19(lo) cytoplasmic IgG+) and CD40+ B1a cells, while preventing an age-related decrease in the B1a cell population expressing a high level of CD5. While ephedrine induced gender-specific immunomodulation in BALB/c mice, increases in the lupus manifestations of anti-dsDNA titers and serum urea nitrogen were not detected. Preadministration of propranolol decreased lupus manifestations and serum levels of IgG and IgE in ephedrine-treated mice, but did not block the shift towards IgG1 production. These findings indicate that ephedrine via beta-AR can exacerbate lupus symptoms in NZM391 mice and that blockade of the beta-ARs on B cells, and not T cells, apparently was of greater importance as the inhibition of lupus symptoms corresponded to an inhibition of immunoglobulin levels, not a change of Th1/Th2 balance.