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

Laboratory of Clinical and Environmental Endocrinology and Immunology, Wadsworth Center, New York State Department of Health, Empire State Plaza, P.O. Box 509, Albany, New York, 12201, USA

T K Mondal

Laboratory of Clinical and Environmental Endocrinology and Immunology, Wadsworth Center, New York State Department of Health, Empire State Plaza, P.O. Box 509, Albany, New York, 12201, USA

L Cao

Laboratory of Clinical and Environmental Endocrinology and Immunology, Wadsworth Center, New York State Department of Health, Empire State Plaza, P.O. Box 509, Albany, New York, 12201, USA

J Kasten-Jolly

Laboratory of Clinical and Environmental Endocrinology and Immunology, Wadsworth Center, New York State Department of Health, Empire State Plaza, P.O. Box 509, Albany, New York, 12201, USA

V C Huber

Laboratory of Clinical and Environmental Endocrinology and Immunology, Wadsworth Center, New York State Department of Health, Empire State Plaza, P.O. Box 509, Albany, New York, 12201, USA

D A Lawrence

Laboratory of Clinical and Environmental Endocrinology and Immunology, Wadsworth Center, New York State Department of Health, Empire State Plaza, P.O. Box 509, Albany, New York, 12201, USA, david.lawrence{at}wadsworth.org

The dietary supplement and adrenergic receptor agonist ephedrine has been a controversial topic as its safety has been questioned. b-adrenergic receptor (b-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 mg/day. Some ephedrine-treated NZM391 mice also were preadministered the b-AR antagonist propranolol to investigate b-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 b-AR can exacerbate lupus symptoms in NZM391 mice and that blockade of the b-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.

Key Words: beta-adrenergic • B1 cells • CD40 • CD5+B cells • ephedrine • NZM strains

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