Abstract
Objective: Rheumatoid arthritis (RA) is the most prevalent autoimmune arthritis. Berberine is an alkaloid isolated from Berberis vulgaris, and its anti-inflammatory effect has been identified.
Methods: Twenty newly diagnosed RA patients and 20 healthy controls participated. Peripheral mononuclear cells were prepared and stimulated with bacterial lipopolysachharide (LPS,1 μg/ml), exposed to different concentrations of berberine (10 and 50μM) and dexamethasone (10-7 M) as a reference. The toxicity of compounds was evaluated by WST-1 assay. The expression of TNF-α and IL-1β was determined by quantitative real-time PCR. Protein level of secreted TNF-α and IL-1β was measured by using ELISA.
Results: Berberine did not have any toxic effect on cells, whereas Lipopolysaccharide (LPS) stimulation caused a noticeable rise in TNF-α and IL-1β production. Berberine markedly downregulated the expression of both TNF-α and IL-1β, and inhibited TNF-α and IL-1β secretion from LPS-stimulated PBMCs.
Discussion: This study provided a molecular basis for anti-inflammatory effect of berberine on human mononuclear cells through the suppression of TNF-a and IL-1secretion. Our findings highlighted the significant inhibitory effect of berberine on proinflammatory responses of mononuclear cells from rheumatoid arthritis individuals, which may be responsible for antiinflammatory property of Barberry. We observed that berberine at high concentration exhibited anti-inflammatory effect in PBMCs of both healthy and patient groups by suppression of TNF-a and IL-1cytokines at both mRNA and protein levels.
Conclusion: Berberine may inhibit the gene expression and production of pro-inflammatory cytokines by mononuclear cells in rheumatoid arthritis and healthy individuals without affecting cell viability. Future studies with a larger sample size are needed to prove the idea.
Keywords: Rheumatoid arthritis, berberine, dexamethasone, TNF-α, IL-1β, mononuclear cells.
Graphical Abstract
[1]
Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 2005; 52(3): 722-32.
[http://dx.doi.org/10.1002/art.20878] [PMID: 15751097]
[http://dx.doi.org/10.1002/art.20878] [PMID: 15751097]
[2]
Bresnihan B. Pathogenesis of joint damage in rheumatoid arthritis. J Rheumatol 1999; 26(3): 717-9.
[PMID: 10090189]
[PMID: 10090189]
[3]
Steiner G, Tohidast-Akrad M, Witzmann G, et al. Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology (Oxford) 1999; 38(3): 202-13.
[http://dx.doi.org/10.1093/rheumatology/38.3.202] [PMID: 10325658]
[http://dx.doi.org/10.1093/rheumatology/38.3.202] [PMID: 10325658]
[4]
Jahani G, Fatemi H. Diseases of muscular, skeletal and connective (Translated in Persian language) Horisons principles of internal medicine: Companion Handbook, tissues 13th ed Author: Harison. 1995; pp. 8-12.
[5]
Mahmoudi M, Zamani Taghizadeh Rabe S, Balali-Mood M, et al. Immunotoxicity induced in mice by subacute exposure to berberine. J Immunotoxicol 2016; 13(2): 255-62.
[http://dx.doi.org/10.3109/1547691X.2015.1058306] [PMID: 26100397]
[http://dx.doi.org/10.3109/1547691X.2015.1058306] [PMID: 26100397]
[6]
Hu PF, Chen WP, Tang JL, Bao JP, Wu LD. Protective effects of berberine in an experimental rat osteoarthritis model. Phytother Res 2011; 25(6): 878-85.
[http://dx.doi.org/10.1002/ptr.3359] [PMID: 21108488]
[http://dx.doi.org/10.1002/ptr.3359] [PMID: 21108488]
[7]
Dharmananda S. New Uses of Berberine: a Valuable Alkaloid from Herbs for" damp-heat" Syndromes: ITM 2005.
[8]
Hayashi K, Minoda K, Nagaoka Y, Hayashi T, Uesato S. Antiviral activity of berberine and related compounds against human cytomegalovirus. Bioorg Med Chem Lett 2007; 17(6): 1562-4.
[http://dx.doi.org/10.1016/j.bmcl.2006.12.085] [PMID: 17239594]
[http://dx.doi.org/10.1016/j.bmcl.2006.12.085] [PMID: 17239594]
[9]
Hu Z, Jiao Q, Ding J, et al. Berberine induces dendritic cell apoptosis and has therapeutic potential for rheumatoid arthritis. Arthritis Rheum 2011; 63(4): 949-59.
[http://dx.doi.org/10.1002/art.30202] [PMID: 21162100]
[http://dx.doi.org/10.1002/art.30202] [PMID: 21162100]
[10]
Sun Y, Xun K, Wang Y, Chen X. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs 2009; 20(9): 757-69.
[http://dx.doi.org/10.1097/CAD.0b013e328330d95b] [PMID: 19704371]
[http://dx.doi.org/10.1097/CAD.0b013e328330d95b] [PMID: 19704371]
[11]
Lin C-C, Yang J-S, Chen J-T, et al. Berberine induces apoptosis in human HSC-3 oral cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway. Anticancer Res 2007; 27(5A): 3371-8.
[PMID: 17970083]
[PMID: 17970083]
[12]
Tanaka T, Metori K, Mineo S, Hirotani M, Furuya T, Kobayashi S. Inhibitory effects of berberine-type alkaloids on elastase. Planta Med 1993; 59(3): 200-2.
[http://dx.doi.org/10.1055/s-2006-959651] [PMID: 8316586]
[http://dx.doi.org/10.1055/s-2006-959651] [PMID: 8316586]
[13]
Kim K-W, Ha K-T, Park C-S, et al. Polygonum cuspidatum, compared with baicalin and berberine, inhibits inducible nitric oxide synthase and cyclooxygenase-2 gene expressions in RAW 264.7 macrophages. Vascul Pharmacol 2007; 47(2-3): 99-107.
[http://dx.doi.org/10.1016/j.vph.2007.04.007] [PMID: 17553752]
[http://dx.doi.org/10.1016/j.vph.2007.04.007] [PMID: 17553752]
[14]
Lee C-H, Chen J-C, Hsiang C-Y, Wu S-L, Wu H-C, Ho T-Y. Berberine suppresses inflammatory agents-induced interleukin-1β and tumor necrosis factor-α productions via the inhibition of IkappaB degradation in human lung cells. Pharmacol Res 2007; 56(3): 193-201.
[http://dx.doi.org/10.1016/j.phrs.2007.06.003] [PMID: 17681786]
[http://dx.doi.org/10.1016/j.phrs.2007.06.003] [PMID: 17681786]
[15]
Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res 2008; 22(8): 999-1012.
[http://dx.doi.org/10.1002/ptr.2399] [PMID: 18618524]
[http://dx.doi.org/10.1002/ptr.2399] [PMID: 18618524]
[16]
Wang Z, Chen Z, Yang S, et al. Berberine ameliorates collagen-induced arthritis in rats associated with anti-inflammatory and anti-angiogenic effects. Inflammation 2014; 37(5): 1789-98.
[http://dx.doi.org/10.1007/s10753-014-9909-y] [PMID: 24803296]
[http://dx.doi.org/10.1007/s10753-014-9909-y] [PMID: 24803296]
[17]
Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31(3): 315-24.
[http://dx.doi.org/10.1002/art.1780310302] [PMID: 3358796]
[http://dx.doi.org/10.1002/art.1780310302] [PMID: 3358796]
[18]
Abd El-Wahab AE, Ghareeb DA, Sarhan EE, Abu-Serie MM, El Demellawy MA. In vitro biological assessment of Berberis vulgaris and its active constituent, berberine: antioxidants, anti-acetylcholinesterase, anti-diabetic and anticancer effects. BMC Complement Altern Med 2013; 13(1): 218.
[http://dx.doi.org/10.1186/1472-6882-13-218] [PMID: 24007270]
[http://dx.doi.org/10.1186/1472-6882-13-218] [PMID: 24007270]
[19]
Rossini M, Rossi E, Bernardi D, et al. Prevalence and incidence of rheumatoid arthritis in Italy. Rheumatol Int 2014; 34(5): 659-64.
[http://dx.doi.org/10.1007/s00296-014-2974-6] [PMID: 24610538]
[http://dx.doi.org/10.1007/s00296-014-2974-6] [PMID: 24610538]
[20]
Silman AJ. Work characteristics, demographic factors and clinical variables could predict work disability in rheumatoid arthritis. Clin Exp Rheumatol 2001; 19(3): 247-8.
[PMID: 11407075]
[PMID: 11407075]
[21]
Uhlig T, Moe RH, Kvien TK. The burden of disease in rheumatoid arthritis. Pharmacoeconomics 2014; 32(9): 841-51.
[http://dx.doi.org/10.1007/s40273-014-0174-6] [PMID: 24859304]
[http://dx.doi.org/10.1007/s40273-014-0174-6] [PMID: 24859304]
[22]
Sweeney SE, Firestein GS. Rheumatoid arthritis: regulation of synovial inflammation. Int J Biochem Cell Biol 2004; 36(3): 372-8.
[http://dx.doi.org/10.1016/S1357-2725(03)00259-0] [PMID: 14687914]
[http://dx.doi.org/10.1016/S1357-2725(03)00259-0] [PMID: 14687914]
[23]
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365(23): 2205-19.
[http://dx.doi.org/10.1056/NEJMra1004965] [PMID: 22150039]
[http://dx.doi.org/10.1056/NEJMra1004965] [PMID: 22150039]
[24]
Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344(12): 907-16.
[http://dx.doi.org/10.1056/NEJM200103223441207] [PMID: 11259725]
[http://dx.doi.org/10.1056/NEJM200103223441207] [PMID: 11259725]
[25]
Butler DM, Maini RN, Feldmann M, Brennan FM. Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist. Eur Cytokine Netw 1995; 6(4): 225-30.
[PMID: 8789287]
[PMID: 8789287]
[26]
Parameswaran N, Patial S. Tumor necrosis factor-α signaling in macrophages. Critical Reviews™ in Eukaryotic Gene Expression 2010; 20(2): 87-103.
[http://dx.doi.org/10.1615/CritRevEukarGeneExpr.v20.i2.10]
[http://dx.doi.org/10.1615/CritRevEukarGeneExpr.v20.i2.10]
[27]
Vincent FB, Morand EF, Murphy K, Mackay F, Mariette X, Marcelli C. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Annals of the rheumatic diseases 2013; 72(2): 165-78.
[28]
Moltó A, Olivé A. Anti-IL-1 molecules: new comers and new indications. Joint Bone Spine 2010; 77(2): 102-7.
[http://dx.doi.org/10.1016/j.jbspin.2009.10.011] [PMID: 20045371]
[http://dx.doi.org/10.1016/j.jbspin.2009.10.011] [PMID: 20045371]
[29]
Westhovens R, Yocum D, Han J, et al. START Study Group. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum 2006; 54(4): 1075-86.
[http://dx.doi.org/10.1002/art.21734] [PMID: 16572442]
[http://dx.doi.org/10.1002/art.21734] [PMID: 16572442]
[30]
Wang Q, Jiang J, Chen W, Jiang H, Zhang Z, Sun X. Targeted delivery of low-dose dexamethasone using PCL-PEG micelles for effective treatment of rheumatoid arthritis. J Control Release 2016; 230: 64-72.
[http://dx.doi.org/10.1016/j.jconrel.2016.03.035] [PMID: 27057749]
[http://dx.doi.org/10.1016/j.jconrel.2016.03.035] [PMID: 27057749]
[31]
Baschant U, Lane NE, Tuckermann J. The multiple facets of glucocorticoid action in rheumatoid arthritis. Nat Rev Rheumatol 2012; 8(11): 645-55.
[http://dx.doi.org/10.1038/nrrheum.2012.166] [PMID: 23045254]
[http://dx.doi.org/10.1038/nrrheum.2012.166] [PMID: 23045254]
[32]
Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 2005; 353(16): 1711-23.
[http://dx.doi.org/10.1056/NEJMra050541] [PMID: 16236742]
[http://dx.doi.org/10.1056/NEJMra050541] [PMID: 16236742]
[33]
Liu SJ, Yin CX, Ding MC, Wang YZ, Wang H. Berberine inhibits tumor necrosis factor-α-induced expression of inflammatory molecules and activation of nuclear factor-κB via the activation of AMPK in vascular endothelial cells. Mol Med Rep 2015; 12(4): 5580-6.
[http://dx.doi.org/10.3892/mmr.2015.4061] [PMID: 26166377]
[http://dx.doi.org/10.3892/mmr.2015.4061] [PMID: 26166377]
[34]
Sarna LK, Wu N, Hwang S-Y, Siow YL, O K. Berberine inhibits NADPH oxidase mediated superoxide anion production in macrophages. Can J Physiol Pharmacol 2010; 88(3): 369-78.
[http://dx.doi.org/10.1139/Y09-136] [PMID: 20393601]
[http://dx.doi.org/10.1139/Y09-136] [PMID: 20393601]
[35]
Shin J-S, Choi H-E, Seo S, Choi J-H, Baek N-I, Lee K-T. Berberine decreased inducible nitric oxide synthase mrna stability through negative regulation of human antigen R in lipopolysaccharide-induced macrophages. J Pharmacol Exp Ther 2016; 358(1): 3-13.
[http://dx.doi.org/10.1124/jpet.115.231043] [PMID: 27189969]
[http://dx.doi.org/10.1124/jpet.115.231043] [PMID: 27189969]
[36]
Shin J-S, Choi H-E, Seo S, Choi J-H, Baek N-I, Lee K-T. Berberine decreased iNOS mRNA stability through negative regulation of HuR in LPS-induced macrophages. J Pharmacol Exp Ther 2016; 385(1): 3-13.
[http://dx.doi.org/10.1124/jpet.115.231043]
[http://dx.doi.org/10.1124/jpet.115.231043]
[37]
Karimi G, Mahmoudi M, Balali-Mood M, Rahnama M, Zamani Taghizadeh Rabe S, Tabasi N, et al. Decreased Levels of Spleen Tissue CD4+ CD25+ Foxp3+ Regulatory T Lymphocytes in Mice Exposed to Berberine. J Acupunct Meridian Stud 2017; 10(2): 109-13.
[http://dx.doi.org/10.1016/j.jams.2016.10.003] [PMID: 28483181]
[http://dx.doi.org/10.1016/j.jams.2016.10.003] [PMID: 28483181]
[38]
Paoletti A, Rohmer J, Ly B, et al. Monocyte/macrophage abnormalities specific to rheumatoid arthritis are linked to mir-155 and are differentially modulated by different TNF inhibitors. J Immunol 2019; 203(7): 1766-75.
[http://dx.doi.org/10.4049/jimmunol.1900386] [PMID: 31484730]
[http://dx.doi.org/10.4049/jimmunol.1900386] [PMID: 31484730]
[39]
You C, Zhang H, Sakharkar AJ, Teppen T, Pandey SC. Reversal of deficits in dendritic spines, BDNF and Arc expression in the amygdala during alcohol dependence by HDAC inhibitor treatment. Int J Neuropsychopharmacol 2014; 17(2): 313-22.
[http://dx.doi.org/10.1017/S1461145713001144] [PMID: 24103311]
[http://dx.doi.org/10.1017/S1461145713001144] [PMID: 24103311]
[40]
Long L, Yu P, Liu Y, et al. Upregulated microRNA-155 expression in peripheral blood mononuclear cells and fibroblast-like synoviocytes in rheumatoid arthritis. Clin Dev Immunol 2013; 2013: 296139.
[http://dx.doi.org/10.1155/2013/296139] [PMID: 24151514]
[http://dx.doi.org/10.1155/2013/296139] [PMID: 24151514]
Article Metrics
38
1