Immunosuppressive Activity of Daphnetin, One of Coumarin Derivatives, Is Mediated through Suppression of NF-κB and NFAT Signaling Pathways in Mouse T Cells
Daphnetin, a plant-derived dihydroxylated derivative of coumarin, is an effective compound extracted from a plant called Daphne Korean Nakai. Coumarin derivates were known for their antithrombotic, anti-inflammatory, and antioxidant activities. The present study was aimed to determine the immunosuppressive effects and the underlying mechanisms of daphnetin on concanavalin A (ConA) induced T lymphocytes in mice. We showed that, in vitro, daphnetin suppressed ConA-induced splenocyte proliferation, influenced production of the cytokines and inhibited cell cycle progression through the G0/G1 transition. The data also revealed that daphnetin could down-regulate activation of ConA induced NF-κB and NFAT signal transduction pathways in mouse T lymphocyte. In vivo, daphnetin treatment significantly inhibited the 2, 4- dinitrofluorobenzene (DNFB) -induced delayed type hypersensitivity (DTH) reactions in mice. Collectively, daphnetin had strong immunosuppressive activity both in vitro and in vivo, suggesting a potential role for daphnetin as an immunosuppressive agent, and established the groundwork for further research on daphnetin.
References
[1]
Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383: 787–793. doi: 10.1038/383787a0
[2]
Snell GI, Westall GP, Paraskeva MA (2013) Immunosuppression and allograft rejection following lung transplantation: evidence to date. Drugs 73: 1793–1813. doi: 10.1007/s40265-013-0136-x
[3]
van Sandwijk MS, Bemelman FJ, Ten Berge IJ (2013) Immunosuppressive drugs after solid organ transplantation. Neth J Med 71: 281–289.
[4]
Pearce EL (2010) Metabolism in T cell activation and differentiation. Curr Opin Immunol 22: 314–320. doi: 10.1016/j.coi.2010.01.018
[5]
Pfeifhofer C, Kofler K, Gruber T, Tabrizi NG, Lutz C, et al. (2003) Protein kinase C theta affects Ca2+ mobilization and NFAT cell activation in primary mouse T cells. J Exp Med 197: 1525–1535. doi: 10.1084/jem.20020234
[6]
Aifantis I, Gounari F, Scorrano L, Borowski C, von Boehmer H (2001) Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-kappaB and NFAT. Nature Immunology 2: 403–409.
[7]
Zhang SD, Yin YX, Wei Q (2010) Immunopotentiation on murine spleen lymphocytes induced by polysaccharide fraction of Panax ginseng via upregulating calcineurin activity. APMIS 118: 288–296. doi: 10.1111/j.1600-0463.2010.02589.x
[8]
Al-Shanti N, Stewart CE (2009) Ca2+/calmodulin-dependent transcriptional pathways: potential mediators of skeletal muscle growth and development. Biol Rev Camb Philos Soc 84: 637–652. doi: 10.1111/j.1469-185x.2009.00090.x
[9]
Ma W, Mishra S, Gee K, Mishra JP, Nandan D, et al. (2007) Cyclosporin A and FK506 inhibit IL-12p40 production through the calmodulin/calmodulin-dependent protein kinase-activated phosphoinositide 3-kinase in lipopolysaccharide-stimulated human monocytic cells. J Biol Chem 282: 13351–13362. doi: 10.1074/jbc.m611522200
[10]
Hughes K, Edin S, Antonsson A, Grundstrom T (2001) Calmodulin-dependent kinase II mediates T cell receptor/CD3- and phorbol ester-induced activation of IkappaB kinase. J Biol Chem 276: 36008–36013. doi: 10.1074/jbc.m106125200
C ND, Anzellotti D, Ibrahim RK, Huner NP, Sarhan F (2003) Daphnetin methylation by a novel O-methyltransferase is associated with cold acclimation and photosystem II excitation pressure in rye. J Biol Chem 278: 6854–6861. doi: 10.1074/jbc.m209439200
[13]
Tu L, Li S, Fu Y, Yao R, Zhang Z, et al. (2012) The therapeutic effects of daphnetin in collagen-induced arthritis involve its regulation of Th17 cells. Int Immunopharmacol 13: 417–423. doi: 10.1016/j.intimp.2012.04.001
[14]
Gao Q, Shan J, Di L, Jiang L, Xu H (2008) Therapeutic effects of daphnetin on adjuvant-induced arthritic rats. J Ethnopharmacol 120: 259–263. doi: 10.1016/j.jep.2008.08.031
[15]
Yesilada E, Taninaka H, Takaishi Y, Honda G, Sezik E, et al. (2001) In vitro inhibitory effects of Daphne oleoides ssp. oleoides on inflammatory cytokines and activity-guided isolation of active constituents. Cytokine 13: 359–364. doi: 10.1006/cyto.2001.0838
[16]
Finn GJ, Creaven BS, Egan DA (2004) Daphnetin induced differentiation of human renal carcinoma cells and its mediation by p38 mitogen-activated protein kinase. Biochem Pharmacol 67: 1779–1788. doi: 10.1016/j.bcp.2004.01.014
[17]
Yang EB, Zhao YN, Zhang K, Mack P (1999) Daphnetin, one of coumarin derivatives, is a protein kinase inhibitor. Biochem Biophys Res Commun 260: 682–685. doi: 10.1006/bbrc.1999.0958
[18]
Jimenez-Orozco FA, Rosales AA, Vega-Lopez A, Dominguez-Lopez ML, Garcia-Mondragon MJ, et al. (2011) Differential effects of esculetin and daphnetin on in vitro cell proliferation and in vivo estrogenicity. Eur J Pharmacol 668: 35–41. doi: 10.1016/j.ejphar.2011.06.024
[19]
Bultynck G, Vermassen E, Szlufcik K, De Smet P, Fissore RA, et al. (2003) Calcineurin and intracellular Ca2+-release channels: regulation or association? Biochem Biophys Res Commun 311: 1181–1193. doi: 10.1016/j.bbrc.2003.08.084
[20]
Wang GJ, Wang HX, Yao YS, Guo LY, Liu P (2012) The role of Ca2+/calmodulin-dependent protein kinase II and calcineurin in TNF-alpha-induced myocardial hypertrophy. Braz J Med Biol Res 45: 1045–1051. doi: 10.1590/s0100-879x2012007500121
[21]
Shifman JM, Choi MH, Mihalas S, Mayo SL, Kennedy MB (2006) Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by calmodulin with two bound calciums. Proc Natl Acad Sci U S A 103: 13968–13973. doi: 10.1073/pnas.0606433103
[22]
Janossy T, Baranyi L, Knulst AC, Vizler C, Benner R, et al. (1993) MHC-specific graft-protective and delayed-type hypersensitivity (DTH) suppressive activity of a CD4+ CD8+, alpha beta T cell receptor (TCR) positive lymphoma isolated from a tolerant mouse. Immunobiology 188: 172–193. doi: 10.1016/s0171-2985(11)80496-1
[23]
Strauss G, Osen W, Debatin KM (2002) Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs. Clin Exp Immunol 128: 255–266. doi: 10.1046/j.1365-2249.2002.01777.x
[24]
Sakuma S, Kato Y, Nishigaki F, Magari K, Miyata S, et al. (2001) Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation mediated IL-6 and IgM production in vitro. Int Immunopharmacol 1: 749–757. doi: 10.1016/s1567-5769(01)00008-x
[25]
Sakuma S, Kato Y, Nishigaki F, Sasakawa T, Magari K, et al. (2000) FK506 potently inhibits T cell activation induced TNF-alpha and IL-1beta production in vitro by human peripheral blood mononuclear cells. Br J Pharmacol 130: 1655–1663. doi: 10.1038/sj.bjp.0703472
[26]
Qu SY, Jiang XL, Zhao XH, Pan DB, Wang XR, et al. (1986) [Antithrombotic effect of daphnetin in the rat]. Yao Xue Xue Bao 21: 498–501.
[27]
Li X (1986) Clinical analysis of the etficacy of daphnetin in the treatment of Burger's Disease in 112 cases. Jilin Medicine 7: 28–29.
[28]
Datta S, Sarvetnick N (2009) Lymphocyte proliferation in immune-mediated diseases. Trends Immunol 30: 430–438. doi: 10.1016/j.it.2009.06.002
[29]
Tian ZQ, Xu YZ, Zhang YF, Ma GF, He M, et al. (2013) Effects of metallothionein-3 and metallothionein-1E gene transfection on proliferation, cell cycle, and apoptosis of esophageal cancer cells. Genet Mol Res 12: 4595–4603.
[30]
Dujovny N, Varghese A, Shen J, Yin D, Ji S, et al. (2002) Acute xenograft rejection mediated by antibodies produced independently of TH1/TH2 cytokine profiles. Am J Transplant 2: 526–534. doi: 10.1034/j.1600-6143.2002.20606.x
[31]
Di Renzo M, Rubegni P, De Aloe G, Paulesu L, Pasqui AL, et al. (1997) Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T-cell lymphoma. Immunology 92: 99–103. doi: 10.1046/j.1365-2567.1997.00325.x
[32]
Gangopadhyay JP, Ikemoto N (2010) Intracellular translocation of calmodulin and Ca2+/calmodulin-dependent protein kinase II during the development of hypertrophy in neonatal cardiomyocytes. Biochem Biophys Res Commun 396: 515–521. doi: 10.1016/j.bbrc.2010.04.129
[33]
Ippoliti GB, Vigano M (2003) [Calcineurin inhibitors and mechanisms that are responsible for the appearance of post-transplant diabetes mellitus]. G Ital Nefrol 20 Suppl 25S11–14.
[34]
Ishiguro K, Green T, Rapley J, Wachtel H, Giallourakis C, et al. (2006) Ca2+/calmodulin-dependent protein kinase II is a modulator of CARMA1-mediated NF-kappaB activation. Mol Cell Biol 26: 5497–5508. doi: 10.1128/mcb.02469-05
[35]
Quesada AJ, Redondo JM (2003) [CA++/ calcineurin/NFAT signaling in endothelial activation and angiogenesis: effects od cyclosporin A ]. Nefrologia 23 Suppl 344–48.
[36]
Lederer JA, Liou JS, Kim S, Rice N, Lichtman AH (1996) Regulation of NF-kappa B activation in T helper 1 and T helper 2 cells. Journal of Immunology 156: 56–63.
[37]
Actor JK, Hwang SA, Olsen M, Zimecki M, Hunter RL Jr, et al. (2002) Lactoferrin immunomodulation of DTH response in mice. Int Immunopharmacol 2: 475–486. doi: 10.1016/s1567-5769(01)00189-8
[38]
Gautam M, Saha S, Bani S, Kaul A, Mishra S, et al. (2009) Immunomodulatory activity of Asparagus racemosus on systemic Th1/Th2 immunity: implications for immunoadjuvant potential. J Ethnopharmacol 121: 241–247. doi: 10.1016/j.jep.2008.10.028
[39]
Huang F, Tang LH, Yu LQ, Ni YC, Wang QM, et al. (2006) In vitro potentiation of antimalarial activities by daphnetin derivatives against Plasmodium falciparum. Biomed Environ Sci 19: 367–370.
[40]
Chen J, Liu X, Shi YP (2004) Determination of daphnetin in Daphne tangutica and its medicinal preparation by liquid chromatography. Analytica Chimica Acta 523: 29–33. doi: 10.1016/j.aca.2004.07.027
