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

Abstract

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.

Keywords

beta-adrenergic B1 cells CD40 CD5+B cells ephedrine NZM strains

Get full access to this article

View all access options for this article.

References

Malecka-Tendera E. Effect of ephedrine and theophylline on weight loss, resting energy expenditure and lipoprotein lipase activity in obese over-fed rats . Int J Obes Relat Metab Disord 1993; 17: 343-347 .

Molnar D , Torok K , Erhardt E , Jeges S. Safety and efficacy of treatment with an ephedrine/caffeine mixture. The first double-blind placebo controlled pilot study in adolescents . Int J Obes Relat Meta. Disord 2000; 24: 1573-1578 .

Bell DG , Jacobs I , Ellerington K. Effect of caffeine and ephedrine ingestion on anaerobic exercise performance . Med Sci Sports Exerc 2001; 33: 1399-1403 .

Samenuk D , Link MS , Homoud MK et al. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine . Mayo Clin Proc 2002; 77: 12-16 .

Fairchild MD , Alles GA. The central locomotor activity and acute toxicity of the ephedrine and norephedrine isomers in mice . J Pharmacol Exp Ther 1967; 158: 135-139 .

Drug Facts and Comparisons. 2001 annual EFacts CD-Rom St. Louis, MO: Facts and Comparison, Inc .

Ephedrine: Fast Facts Do It Now Foundation. 2002. www.doitnow.org (last accessed 25 November 2004).

Gluck T , Oertel M , Reber T , Zietz B , Scholmerich J , Straub RH. Altered function of the hypothalamic stress axes in patients with moderately active systemic lupus erythematosus. I. The hypothalamus-autonomic nervous system axis . J Rheumatol 2000; 27: 903-910 .

Shanks N , Moore PM , Perks P , Lightman SL. Alterations in hypothalamic pituitary-adrenal function correlated with the onset of murine SLE in MRL +/+ and lpr/lpr . Brain Behav Immun 1999; 13: 348-360 .

10.

Pettinger WA , Mitchell HC. Side effects of vasodilator therapy . Hypertension 1988; 11: 34-36 .

11.

McGuiness M , Frye RA , Deng JS. Atenelol-induced lupus erythematosus . J Am Acad Dermatol 1997; 37: 298-299 .

12.

Herrmann M , Scholmerich J , Straub RH. Stress and rheumatic diseases . Rheum Dis Clin North Am 2000; 26: 737-763 .

13.

Colburn K , Boucek R , Gusewitch G , Wong A , Wat P , Weeks D. Beta-adrenergic receptor stimulation increases anti-DNA antibody production in MRL/1pr mice . J Rheumatol 1990; 17: 138-141 .

14.

Kohm AP , Sanders VM. Norepinephrine and b2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo . Pharmacol Rev 2001; 53: 487-525 .

15.

Gage JR , Fonarow G , Hamilton M , Widawski M , Martinez-Maza O , Vredevoe DL. Beta blocker and angiotensin-converting enzyme inhibitor therapy is associated with decreased Th1/Th2 cytokine ratios and inflammatory cytokine production in patients with chronic heart failure . Neuroimmunomodulation 2004; 11: 173-180 .

16.

Hudson CA , Cao L , Kasten-Jolly J , Kirkwood JN , Lawrence DA. Susceptibility of lupus-prone NZM mouse strains to lead exacerbation of systemic lupus erythematosus symptoms . J Toxicol Environ Health A 2003; 66: 895-918 .

17.

Heo Y , Lee WT , Lawrence DA. Differential effects of lead and cAMP on development and activities of Th1- and Th2-lymphocytes . Toxicol Sci 1998; 43: 172-185 .

18.

Morimoto I. A study on immunological effects of L-canavanine . Kobe J Med Sci 1989; 35: 287-298 .

19.

Takemura H , Hatta S , Yamada K , Ohshika H. Beta-adrenergic receptor-mediated calcium mobilization in the human Jurkat T cell line . Life Sci 1995; 56: 1443-1454 .

20.

Malinow MR , Bardana EJ, Jr , Pirofsky B , Craig S , McLaughlin P. Systemic lupus erythematosus-like syndrome in monkeys fed alfalfa sprouts: role of a nonprotein amino acid . Science 1982; 216: 415-417 .

21.

Fajka-Boja R , Hidvegi M , Shoenfeld Y et al. Fermented wheat germ extract induces apoptosis and downregulation of major histocompatibility complex class I proteins in tumor T and B cell lines . Int J Oncol 2002; 20: 563-570 .

22.

Ehrenfeld M , Blank M , Schoenfeld Y , Hidvegi M. AVEMAR (a new benzoquine-containing natural product) administration interferes with the Th2 response in experimental SLE and promotes amelioration of the disease . Lupus 2001; 10: 622-627 .

23.

Borum ML. Fulminant exacerbation of autoimmune hepatitis after the use of ma huang . Am J Gastroenterol 2001; 96: 1654-1655 .

24.

Youssef WI , Tavill AS. Connective tissue diseases and the liver . J Clin Gastroenterol 2002; 35: 345-349 .

25.

Wooten MR , Khangure MS , Murphy MJ. Intracerebral hemorrhage and vasculitis related to ephedrine abuse . Ann Neurol 1983; 13: 337-340 .

26.

Rudofsky UH , Evans BD , Balaban SL , Mottironi VD , Gabrielsen AE. Differences in expression of lupus nephritis in New Zealand mixed H-2z homozygous inbred strains of mice derived from New Zealand black and New Zealand white mice. Origins and initial characterization . Lab Invest 1993; 68: 419-426 .

27.

Mohan C , Morel L , Yang P et al. Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies . J Clin Invest 1999; 103: 1685-1695 .

28.

Mohan C , Morel L , Yang P , Wakeland EK. Genetic dissection of systemic lupus erythematosus pathogenesis: Sle2 on murine chromo-some 4 leads to B cell hyperactivity . J Immunol 1997; 159: 454-465 .

29.

Mohan C , Morel L , Yang P , Wakeland EK. Accumulation of splenic B1a cells with potent antigen-presenting capability in NZM2410 lupus-prone mice . Arthritis Rheum 1998; 41: 1652-1662 .

30.

Rudofsky UH , Lawrence DA. New Zealand mixed mice: a genetic systemic lupus erythematosus model for assessing environmental effects . Environ Health Perspect 1999; 107: 713-721 .

31.

Heo Y , Lee WT , Lawrence DA. In vivo the environmental pollutants lead and mercury induce oligoclonal T cell responses skewed toward type-2 reactivities . Cell Immunol 1997; 179: 185-195 .

32.

Lawrence DA. In vivo and in vitro effects of lead on humoral and cell mediated immunity . Infect Immun 1981; 31: 136-143 .

33.

Harada Y , Kawano MM , Huang N et al. Identification of early plasma cells in peripheral blood and their clinical significance . Br J Haematol 1996; 92: 184-191 .

34.

Arce E , Jackson DG , Gill MA , Bennett LB , Banchereau J , Pascual V. Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus . Eur J Immunol 2001; 31: 2726-2732 .

35.

Youinou P , Mackenzie LE , Lamour A , Mageed RA , Lydyard PM. Human CD5-positive B cells in lymphoid malignancy and connective tissue diseases . Eur J Clin Invest 1993; 23: 139-150 .

36.

Powell T , Hsu FF , Turk J , Hruska K. Ma-huang strikes again:ephedrine nephrolithiasis . Am J Kidney Dis 1998; 32: 153-159 .

37.

Kimberly RP , Gill JR Jr , Bowden RE , Keiser HR , Plotz PH. Elevated urinary prostaglandins and the effects of aspirin on renal function in lupus erythematosus . Ann Intern Med 1978; 89: 336-341 .

38.

Hayashi T , Hasegawa K , Ohta A , Maeda K. Reduction of serum interferon (IFN) gamma concentration and lupus development in NZB NZWF(1)mice by lactic dehydrogenase virus infection . J Comp Pathol 2001; 125: 285-291 .

39.

Sanmarti R , Collado A , Gratacos J et al. Reduced serum creatine kinase activity in inflammatory rheumatic diseases . J Rheumatol 1996; 23: 310-312 .

40.

Lee YH , Choi SJ , Ji JD , Song GG. Serum creatine kinase in patients with rheumatic diseases . Clin Rheumatol 2000; 19: 296-300 .

41.

Heo Y , Parson PJ , Lawrence DA. Lead differentially modifies cytokine production in vitro and in vivo . Toxicol Appl Pharmacol 1996; 138: 149-157 .

42.

Kotzin BL , Kozora E. Anti-DNA meets NMDA in neuropsychiatric lupus . Nat Med 2001; 7: 1175-1176 .

43.

Kowal C , DeGiorgio LA , Nakaoka T et al. Cognition and immunity: antibody impairs memory . Immunity 2004; 21: 179-188 .

44.

Cassese, G. , Lindenau S , de Boer B et al. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells . Euro J Immunol 2001; 120: 10-18 .

45.

Rudick RA , Eskin TA. Neuropathological features of a lupus-like disorder in autoimmune mice . Ann Neurol 1983; 14: 325-332 .

46.

Kaneko Y , Hirose S , Abe M , Yagita H , Okumura K , Shirai T. CD40 mediated stimulation of B1 and B2 cells: implication in autoantibody production in murine lupus . Eur J Immunol 1996; 26: 3061-3065 .

47.

Raman C. CD5, an important regulator of lymphocyte selection and immune tolerance . Immunol Res 2002; 26: 255-263 .

48.

Dahl ME , Dabbagh K , Liggitt D , Kim S , Lewis DB. Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells . Nat Immunol 2004; 5: 337-343 .

49.

Cao L , Hudson CA , Lawrence DA. Acute cold/restraint stress inhibits host resistance to Listeria monocytogenes via beta1-adrenergic receptors . Brain Behav Immun 2003; 17: 121-133 .

50.

Fireman P. Understanding asthma pathophysiology . Allergy Asthma Proc 2003; 24: 79-83 .

51.

Wozniacka A , Sysa-Jedrzejowska A , Robak E , Samochocki Z , Zak-Prelich M. Allergic diseases, drug adverse reactions and total immunoglobulin E levels in lupus erythematosus patients . Mediators Inflamm 2003; 12: 95-99 .

52.

Lord GM , Matarese G , Howard JK , Baker RJ , Bloom SR , Lechler RI. Leptin modulates the T-cell immune response and reverses starvation induced immunosuppression . Nature 1988; 394: 897-901 .

53.

Szekeres-Bartho J. Immunological relationship between the mother and the fetus . Int Rev Immunol 2002; 21: 471-495 .