Plumbagin(PL), a herbal compound derived from roots of the medicinal plant Plumbago zeylanica, has been shown to have immunosuppressive properties. Present report describes that PL is a potent novel agent in control of encephalitogenic T cell responses and amelioration of mouse experimental autoimmune encephalomyelitis (EAE), through down-regulation of JAK-STAT pathway. PL was found to selectively inhibit IFN-γ and IL-17 production by CD4+ T cells, which was mediated through abrogated phosphorylation of JAK1 and JAK2. Consistent with IFN-γ and IL-17 reduction was suppressed STAT1/STAT4/T-bet pathway which is critical for Th1 differentiation, as well as STAT3/ROR pathway which is essential for Th17 differentiation. In addition, PL suppressed pro-inflammatory molecules such as iNOS, IFN-γ and IL-6, accompanied by inhibition of IκB degradation as well as NF-κB phosphorylation. These data give new insight into the novel immune regulatory mechanism of PL and highlight the great value of this kind of herb compounds in probing the complex cytokine signaling network and novel therapeutic targets for autoimmune diseases.
References
[1]
Becher B, Bechmann I, Greter M (2006) Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. J Mol Med 84: 532–543.
[2]
Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129: 1953–1971.
[3]
Tsunoda I, Fujinami RS (1996) Two models for multiple sclerosis: experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis virus. J Neuropathol Exp Neurol 55: 673–686.
[4]
Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, et al. (2001) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294: 1731–1735.
[5]
Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50: 389–400.
[6]
Vogt J, Paul F, Aktas O, Muller-Wielsch K, Dorr J, et al. (2009) Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis. Ann Neurol 66: 310–322.
[7]
Dong C, Flavell RA (2000) Cell fate decision: T-helper 1 and 2 subsets in immune responses. Arthritis Res 2: 179–188.
[8]
Glimcher LH, Murphy KM (2000) Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev 14: 1693–1711.
[9]
Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24: 677–688.
[10]
Dong C (2006) Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat Rev Immunol 6: 329–333.
[11]
Murphy KM, Reiner SL (2002) The lineage decisions of helper T cells. Nat Rev Immunol 2: 933–944.
[12]
Liu X, Lee YS, Yu CR, Egwuagu CE (2008) Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases. J Immunol 180: 6070–6076.
[13]
Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, et al. (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178: 4901–4907.
[14]
Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, et al. (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100: 655–669.
[15]
Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, et al. (2008) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29: 44–56.
[16]
Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, et al. (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28: 29–39.
[17]
Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9: 798–809.
[18]
Farooqi N, Gran B, Constantinescu CS (2010) Are current disease-modifying therapeutics in multiple sclerosis justified on the basis of studies in experimental autoimmune encephalomyelitis? J Neurochem 115: 829–844.
[19]
Tilak JC, Adhikari S, Devasagayam TP (2004) Antioxidant properties of Plumbago zeylanica, an Indian medicinal plant and its active ingredient, plumbagin. Redox Rep 9: 219–227.
[20]
Demma J, Hallberg K, Hellman B (2009) Genotoxicity of plumbagin and its effects on catechol and NQNO-induced DNA damage in mouse lymphoma cells. Toxicol In Vitro 23: 266–271.
[21]
Checker R, Sharma D, Sandur SK, Khanam S, Poduval TB (2009) Anti-inflammatory effects of plumbagin are mediated by inhibition of NF-kappaB activation in lymphocytes. Int Immunopharmacol 9: 949–958.
[22]
Ahmad A, Banerjee S, Wang Z, Kong D, Sarkar FH (2008) Plumbagin-induced apoptosis of human breast cancer cells is mediated by inactivation of NF-kappaB and Bcl-2. J Cell Biochem 105: 1461–1471.
[23]
Jackson JK, Higo T, Hunter WL, Burt HM (2008) Topoisomerase inhibitors as anti-arthritic agents. Inflamm Res 57: 126–134.
[24]
McKallip RJ, Lombard C, Sun J, Ramakrishnan R (2010) Plumbagin-induced apoptosis in lymphocytes is mediated through increased reactive oxygen species production, upregulation of Fas, and activation of the caspase cascade. Toxicol Appl Pharmacol 247: 41–52.
[25]
Shih YW, Lee YC, Wu PF, Lee YB, Chiang TA (2009) Plumbagin inhibits invasion and migration of liver cancer HepG2 cells by decreasing productions of matrix metalloproteinase-2 and urokinase- plasminogen activator. Hepatol Res 39: 998–1009.
[26]
Mossa JS, El-Feraly FS, Muhammad I (2004) Antimycobacterial constituents from Juniperus procera, Ferula communis and Plumbago zeylanica and their in vitro synergistic activity with isonicotinic acid hydrazide. Phytother Res 18: 934–937.
[27]
Dzoyem JP, Tangmouo JG, Lontsi D, Etoa FX, Lohoue PJ (2007) In vitro antifungal activity of extract and plumbagin from the stem bark of Diospyros crassiflora Hiern (Ebenaceae). Phytother Res 21: 671–674.
[28]
Sandur SK, Ichikawa H, Sethi G, Ahn KS, Aggarwal BB (2006) Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) suppresses NF-kappaB activation and NF-kappaB-regulated gene products through modulation of p65 and IkappaBalpha kinase activation, leading to potentiation of apoptosis induced by cytokine and chemotherapeutic agents. J Biol Chem 281: 17023–17033.
[29]
Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, et al. (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177: 566–573.
[30]
Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, et al. (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6: 1123–1132.
[31]
Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, et al. (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8: 950–957.
[32]
Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, et al. (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30: 576–587.
[33]
Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH (2010) T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 162: 1–11.
[34]
Ivashkiv LB, Hu X (2004) Signaling by STATs. Arthritis Res Ther 6: 159–168.
[35]
Lovett-Racke AE, Yang Y, Racke MK (2011) Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis? Biochim Biophys Acta 1812: 246–251.
[36]
Zhou L, Ivanov , Spolski R, Min R, Shenderov K, et al. (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8: 967–974.
[37]
Jetten AM (2009) Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 7: e003.
[38]
Battle TE, Frank DA (2002) The role of STATs in apoptosis. Curr Mol Med 2: 381–392.
[39]
Hagihara K, Nishikawa T, Sugamata Y, Song J, Isobe T, et al. (2005) Essential role of STAT3 in cytokine-driven NF-kappaB-mediated serum amyloid A gene expression. Genes Cells 10: 1051–1063.
