Download PDF
Planta Med 2017; 83(08): 693-700
DOI: 10.1055/s-0042-122783
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Parthenolide Modulates Immune Response in Cells from C57BL/6 Mice Induced with Experimental Autoimmune Encephalomyelitis

Lara Soares Aleixo de Carvalho
1   Departamento de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Juiz de Fora, Brasil
,
Lívia Beatriz Almeida Fontes
1   Departamento de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Juiz de Fora, Brasil
,
Matheus Coutinho Gazolla
1   Departamento de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Juiz de Fora, Brasil
,
Débora dos Santos Dias
1   Departamento de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Juiz de Fora, Brasil
,
Maria Aparecida Juliano
2   Departamento de Biofísica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brasil
,
Gilson Costa Macedo
3   Departamento de Parasitologia, Microbiologia e Imunologia, Universidade Federal de Juiz de Fora, Juiz de Fora, Brasil
,
José Otávio do Amaral Corrêa
1   Departamento de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Juiz de Fora, Brasil
,
Ademar A. Da Silva Filho
1   Departamento de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Juiz de Fora, Brasil
› Author Affiliations
Further Information

Publication History

received 20 July 2016
revised 21 November 2016

accepted 25 November 2016

Publication Date:
20 December 2016 (online)

    Permissions and Reprints

Abstract

Multiple sclerosis is a chronic inflammatory and autoimmune disease of the central nervous system that affects more than 2.5 million people worldwide. Experimental autoimmune encephalomyelitis is a murine autoimmune disease used to study multiple sclerosis. Parthenolide, a natural sesquiterpene lactone found in Tanacetum parthenium L., is known for its strong anti-inflammatory activity. Herein, we have investigated the in vitro immunomodulatory effects of parthenolide on cytokine production and nitric oxide in cultured cells from myelin oligodendrocyte glycoprotein 35–55 amino acid peptide mice. Experimental autoimmune encephalomyelitis was induced in C57BL/6 mice with myelin oligodendrocyte glycoprotein 35–55 amino acid peptide, and parthenolide was isolated from T. parthenium. Splenocytes and peritoneal cells were obtained from experimental autoimmune encephalomyelitis-induced mice and incubated with parthenolide (1, 5, and 20 µM). After in vitro treatment with parthenolide, supernatants were collected, and nitric oxide and cytokines were measured. The results suggested that parthenolide may regulate the activity of Th17 and Th1 cells, mainly by decreasing IL-17, TNF-α, and interferon gamma production. This modulation may be related to the lower levels of IL-12p40 and IL-6 after treatment with parthenolide. It was shown, for the first time, that parthenolide presents in vitro immunomodulatory effects on inflammatory mediators produced by cells from experimental autoimmune encephalomyelitis-induced mice.

Key words

parthenolide - Tanacetum parthenium - Asteraceae - multiple sclerosis - experimental autoimmune encephalomyelitis - IL-17
 

  • References

  • 1 Frohman EM, Racke MK, Raine CS. Multiple sclerosis – the plaque and its pathogenesis. N Engl J Med 2006; 354: 942-955
    CrossrefPubMedGoogle Scholar
  • 2 Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000; 343: 938-952
    CrossrefPubMedGoogle Scholar
  • 3 Shen R, Deng W, Li C, Zeng G. A natural flavonoid glucoside icariin inhibits Th1 and Th17 cell differentiation and ameliorates experimental autoimmune encephalomyelitis. Int Immunopharmacol 2015; 24: 224-231
    CrossrefPubMedGoogle Scholar
  • 4 Dutra RC, De Souza PRC, Bento AF, Marcon R, Bicca MA, Pianowski LF, Calixto JB. Euphol prevents experimental autoimmune encephalomyelitis in mice: evidence for the underlying mechanisms. Biochem Pharmacol 2012; 83: 531-542
    CrossrefPubMedGoogle Scholar
  • 5 Constantinescu CS, Farooqi N, OʼBrien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 2011; 164: 1079-1106
    CrossrefPubMedGoogle Scholar
  • 6 Fontes LBA, Dias DS, De Carvalho LSA, Mesquita HL, Reis LS, Dias AT, Da Silva Filho AA, Corrêa JOA. Immunomodulatory effects of licochalcone A on experimental autoimmune encephalomyelitis. J Pharm Pharmacol 2014; 66: 886-894
    PubMedGoogle Scholar
  • 7 Dias DS, Fontes LBA, Crotti AEM, Aarestrup BJV, Aarestrup FM, Da Silva Filho AA, Corrêa JOA. Copaiba oil suppresses inflammatory cytokines in splenocytes of C57BL/6 mice induced with experimental autoimmune encephalomyelitis (EAE). Molecules 2014; 19: 12814-12826
    CrossrefPubMedGoogle Scholar
  • 8 Qin X, Guo BT, Wan B, Fang L, Lu L, Wu L, Zang YQ, Zhang JZ. Regulation of Th1 and Th17 cell differentiation and amelioration of experimental autoimmune encephalomyelitis by natural product compound berberine. J Immunol 2010; 185: 1855-1863
    CrossrefPubMedGoogle Scholar
  • 9 Pareek A, Suthar M, Rathore GS, Bansal V. Feverfew (Tanacetum parthenium L.): A systematic review. Pharmacogn Rev 2011; 5: 103-110
    CrossrefPubMedGoogle Scholar
  • 10 Sumner H, Salan U, Knight DW, Hoult JR. Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew. Involvement of sesquiterpene lactones and other components. Biochem Pharmacol 1992; 43: 2313-2320
    CrossrefPubMedGoogle Scholar
  • 11 Zhao ZJ, Xiang JY, Liu L, Huang XL, Gan HT. Parthenolide, an inhibitor of the nuclear factor-kB pathway, ameliorates dextran sulfate sodium-induced colitis in mice. Int Immunopharmacol 2012; 12: 169-174
    CrossrefPubMedGoogle Scholar
  • 12 Magni P, Ruscica M, Dozio E, Rizzi E, Beretta G, Facino RM. Parthenolide inhibits the LPS-induced secretion of IL-6 and TNF-α and NF-kB nuclear translocation in BV-2 microglia. Phytother Res 2012; 26: 1405-1409
    CrossrefPubMedGoogle Scholar
  • 13 Kwok BHB, Koh B, Ndubuisi MI, Elofsson M, Crews CM. The anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IκB kinase. Chem Biol 2001; 8: 759-766
    CrossrefPubMedGoogle Scholar
  • 14 Carlisi D, DʼAnneo A, Angileri L, Lauricella M, Emanuele S, Santulli A, Vento R, Tesoriere G. Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3 activation. J Cell Physiol 2011; 226: 1632-1641
    CrossrefPubMedGoogle Scholar
  • 15 Orhan IE, Tosun F, Lpinar ARG, Kartal M, Duran A, Mihoglugil F, Akalgan D. LC–MS quantification of parthenolide and cholinesterase inhibitory potential of selected Tanacetum L. (Emend. Briq.) taxa. Phytochem Lett 2015; 11: 347-352
    CrossrefPubMedGoogle Scholar
  • 16 Kim SL, Kim SH, Trang KTT, Kim IH, Lee SO, Lee ST, Kim DG, Kang SB, Kim SW. Synergistic antitumor effect of 5-fluorouracil in combination with parthenolide in human colorectal cancer. Cancer Lett 2013; 335: 479-486
    CrossrefPubMedGoogle Scholar
  • 17 Ku C, Lin J. Anti-inflammatory effects of 27 selected terpenoids compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes. Food Chem 2013; 141: 1104-1113
    CrossrefPubMedGoogle Scholar
  • 18 Hofman FM, Hinton DR, Johnson K, Merrill JE. Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 1989; 170: 607-612
    CrossrefPubMedGoogle Scholar
  • 19 Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 2007; 13: 1173-1175
    CrossrefPubMedGoogle Scholar
  • 20 Murphy AC, Lalor SJ, Lynch MA, Mills KHG. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun 2010; 24: 641-651
    CrossrefPubMedGoogle Scholar
  • 21 Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 2006; 177: 566-573
    CrossrefPubMedGoogle Scholar
  • 22 Uyttenhove C, Van Snick J. Development of an anti-IL-17A auto-vaccine that prevents experimental auto-immune encephalomyelitis. Eur J Immunol 2006; 36: 2868-2874
    CrossrefPubMedGoogle Scholar
  • 23 Gijbels K, Brocke S, Abrams JS, Steinman L. Administration of neutralizing antibodies to interleukin-6 (IL-6) reduces experimental autoimmune encephalomyelitis and is associated with elevated levels of IL-6 bioactivity in central nervous system and circulation. Mol Med 1995; 1: 795-805
    PubMedGoogle Scholar
  • 24 Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007; 8: 967-974
    CrossrefPubMedGoogle Scholar
  • 25 Liu N, Kan QC, Zhang XJ, Xv YM, Zhang S, Zhang GX, Zhu L. Upregulation of immunomodulatory molecules by matrine treatment inexperimental autoimmune encephalomyelitis. Exp Mol Pathol 2014; 97: 470-476
    CrossrefPubMedGoogle Scholar
  • 26 Khoury SJ, Hancock WW, Weiner HL. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor 0, interleukin 4, and prostaglandin E expression in the brain. J Exp Med 1992; 176: 1355-1364
    CrossrefPubMedGoogle Scholar
  • 27 Muramatsu R, Kubo T, Mori M, Nakamura Y, Fujita Y, Akutsu T, Okuno T, Taniguchi J, Kumanogoh A, Yoshida M, Mochizuki H, Kuwabara S, Yamashita T. RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis. Nat Med 2011; 17: 488-494
    CrossrefPubMedGoogle Scholar
  • 28 Li-Weber M, Giaisi M, Treiber MK, Krammer PH. The anti-inflammatory sesquiterpene lactone parthenolide suppresses IL-4 gene expression in peripheral blood T cells. Eur J Immunol 2002; 32: 3587-3597
    CrossrefPubMedGoogle Scholar
  • 29 Falcone M, Rajan AJ, Bloom BR, Brosnan CF. A critical role for IL-4 in regulating disease severity in experimental allergic encephalomyelitis as demonstrated in IL-4-deficient C57BL/6 mice and BALB/c mice. J Immunol 1998; 160: 4822-4830
    PubMedGoogle Scholar
  • 30 Dey S, Sarkar M, Giri B. Anti-inflammatory and anti-tumor activities of parthenolide: an update. J Chem Biol Ther 2016; 2: 1-6
    PubMedGoogle Scholar
  • 31 OʼNeill LA, Barrett ML, Lewis GP. Extracts of feverfew inhibit mitogen-induced human peripheral blood mononuclear cell proliferation and cytokine mediated responses: a cytotoxic effect. Br J Clin Pharmacol 1987; 23: 81-83
    CrossrefPubMedGoogle Scholar
  • 32 Gutcher I, Becher B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest 2007; 117: 1119-1127
    CrossrefPubMedGoogle Scholar
  • 33 Zhang J, Benedek G, Bodhankar S, Lapato A, Vandenbark AA, Offner H. IL-10 producing B cells partially restore E2-mediated protection against EAE in PD-L1 deficient mice. J Neuroimmunol 2015; 285: 129-136
    CrossrefPubMedGoogle Scholar
  • 34 Kang BY, Chung SW, Kim TS. Inhibition of interleukin-12 production in lipopolysaccharide-activated mouse macrophages by parthenolide, a predominant sesquiterpene lactone in Tanacetum parthenium: involvement of nuclear factor-kappaB. Immunol Lett 2001; 77: 159-163
    CrossrefPubMedGoogle Scholar
  • 35 Uchi H, Arrighi JF, Aubry JP, Furue M, Hauser C. The sesquiterpene lactone parthenolide inhibits LPS- but not TNF-alpha-induced maturation of human monocyte-derived dendritic cells by inhibition of the p38 mitogen-activated protein kinase pathway. J Allergy Clin Immunol 2002; 110: 269-276
    CrossrefPubMedGoogle Scholar
  • 36 Brok HPM, Van Meurs M, Blezer E, Schantz A, Peritt D, Treacy G, Laman JD, Bauer J, Hart BA. Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p40 monoclonal antibody. J Immunol 2002; 169: 6554-6563
    CrossrefPubMedGoogle Scholar
  • 37 Gran B, Zhang GX, Yu S, Li J, Chen XH, Ventura ES, Kamoun M, Rostami A. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol 2002; 169: 7104-7110
    CrossrefPubMedGoogle Scholar
  • 38 Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest 2006; 116: 1218-1222
    CrossrefPubMedGoogle Scholar
  • 39 Pautz A, Art J, Hahn S, Nowag S, Voss C, Kleinert H. Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide 2010; 23: 75-93
    CrossrefPubMedGoogle Scholar
  • 40 Leiper J, Nandi M. The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nat Rev Drug Discov 2011; 10: 277-291
    CrossrefPubMedGoogle Scholar
  • 41 Ljubisavljevic S, Stojanovic I, Pavlovic R, Sokolovic D, Pavlovic D, Cvetkovic T, Stevanovic I. Modulation of nitric oxide synthase by arginase and methylated arginines during the acute phase of experimental multiple sclerosis. J Neurol Sci 2012; 318: 106-111
    CrossrefPubMedGoogle Scholar
  • 42 Cross AH, Misko TP, Lin RF, Hickey WF, Trotter JL, Tilton RG. Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. J Clin Invest 1994; 93: 2684-2690
    CrossrefPubMedGoogle Scholar
  • 43 Fukuda K, Hibiya Y, Mutoh M, Ohno Y, Yamashita K, Akao S, Fujiwara H. Inhibition by parthenolide of phorbol ester-induced transcriptional activation of inducible nitric oxide synthase gene in a human monocyte cell line THP-1. Biochem Pharmacol 2000; 60: 595-600
    CrossrefPubMedGoogle Scholar
  • 44 Fiebich BL, Lieb K, Engels S, Heinrich M. Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J Neuroimmunol 2002; 132: 18-24
    CrossrefPubMedGoogle Scholar
  • 45 Herrera F, Martin V, Rodriguez-Blanco J, García-Santos G, Antolín I, Rodriguez C. Intracellular redox state regulation by parthenolide. Biochem Biophys Res Commun 2005; 332: 321-325
    CrossrefPubMedGoogle Scholar
  • 46 Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15 N] nitrate in biological fluids. Anal Biochem 1982; 126: 131-138
    CrossrefPubMedGoogle Scholar