Abstract
Isoliquiritigenin (ISL) is an important flavonoid component of licorice and has been reported to possess anti-inflammatory and antioxidant properties, but its exact mechanism of action remains poorly understood. Previously, we demonstrated that ISL could suppress IL-6 expression in multiple myeloma. Here, we further characterized the anti-inflammatory effects of ISL in several psoriasis models, including the keratin 14/vascular endothelial growth factor (VEGF) transgenic mouse, the imiquimod (IMQ)-induced psoriasis-like mouse, and the human keratinocytes HaCaT and NHEK in vitro. We found that ISL ameliorated the inflammatory process in psoriasis models but not in their respective controls. Moreover, the anti-inflammatory effects of ISL were attributed to the suppression of nuclear factor-κB (NF-κB) activity, which consequently resulted in the reduction of pro-inflammation cytokines IL-6 and IL-8 expression. In conclusion, ISL exhibited anti-inflammatory effects in psoriasis models, by downregulating IL-6 and IL-8 via suppression of NF-κB activity, suggesting that ISL might serve as a potential candidate for treatment of psoriasis and other autoimmune inflammatory diseases.
Key message
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ISL could ameliorate the inflammatory process of psoriasis.
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ISL could suppress NF-κB and subsequent production of a series of pro-inflammatory cytokines.
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Dual-inhibitory activity against IL-6 and IL-8 of ISL is implemented via inhibiting NF-κB.
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ISL exerts no inhibitory effects on normal human keratinocytes or wild-type Balb/c mice, implying its low toxicity and safety.
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References
Shibata S (2000) A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zsshi 120:849–862
Olukoga A, Donaldson D (1998) Historical perspectives on health - the history of liquorice: the plant, its extract, cultivation, commercialisation and etymology. J R Soc Health 118:300–304
Reid DP (1995) A handbook of Chinese healing Herbs. SHAMBHALA PUB Incorporated.
Huseman PA (1944) Licorice: putting a weed to work. Heffer & Sons, Ltd, London
Wang ZY, Nixon DW (2001) Licorice and cancer. Nutr Cancer 39:1–11
Gibson M (1978) Glycyrrhiza in old and new perspectives. Lloydia 41:348–354
Fenwick G, Lutomski J, Nieman C (1990) Liquorice, Glycyrrhiza glabra L.—composition, uses and analysis. Food Chem 38:119–143
Fu B, Li H, Wang X, Lee FS, Cui S (2005) Isolation and identification of flavonoids in licorice and a study of their inhibitory effects on tyrosinase. J Agr Food Chem 53:7408–7414
Yamamoto S, Aizu E, Jiang H, Nakadate T, Kiyoto I, Wang JC, Kato R (1991) The potent anti-tumor-promoting agent isoliquiritigenin. Carcinogenesis 12:317–323
Yadav VR, Prasad S, Sung B, Aggarwal BB (2011) The role of chalcones in suppression of NF-kappaB-mediated inflammation and cancer. Int Immunopharmacol 11:295–309
Chen X, Wu Y, Jiang Y, Zhou Y, Wang Y, Yao Y, Yi C, Gou L, Yang J (2012) Isoliquiritigenin inhibits the growth of multiple myeloma via blocking IL-6 signaling. J Mol Med 90:1311–1319
Schon MP, Boehncke WH (2005) Psoriasis. New Engl J Med 352:1899–1912
Cai Y, Shen X, Ding C, Qi C, Li K, Li X, Jala VR, H-g Z, Wang T, Zheng J (2011) Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35:596–610
Christophers E (2001) Psoriasis—epidemiology and clinical spectrum. Clin Exp Dermatol 26:314–320
Nestle FO, Kaplan DH, Barker J (2009) Psoriasis. New Engl J Med 361:496–509
Gottlieb AB (2005) Psoriasis: emerging therapeutic strategies. Nat Rrev Drug Discov 4:19–34
Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. J Clin Invest 107:7–11
Barnes PJ, Karin M (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. New Engl J Med 336:1066–1071
Goldminz A, Au S, Kim N, Gottlieb A, Lizzul P (2013) NF-κB: an essential transcription factor in psoriasis. J Dermatol Sci 69:89–94
Grossman RM, Krueger J, Yourish D, Granelli-Piperno A, Murphy DP, May LT, Kupper TS, Sehgal PB, Gottlieb AB (1989) Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci U S A 86:6367–6371
Huggenberger R, Ullmann S, Proulx ST, Pytowski B, Alitalo K, Detmar M (2010) Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med 207:2255–2269
Wang H, Peters T, Sindrilaru A, Scharffetter-Kochanek K (2009) Key role of macrophages in the pathogenesis of CD18 hypomorphic murine model of psoriasis. J Invest Dermatol 129:1100–1114
Schon MP (1999) Animal models of psoriasis—what can we learn from them? J Invest Dermatol 112:405–410
Detmar M, Brown LF, Schön MP, Elicker BM, Velasco P, Richard L, Fukumura D, Monsky W, Claffey KP, Jain RK (1998) Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J Invest Dermatol 111:1–6
Baker B, Brent L, Valdimarsson H, Powles A, Al‐Imara L, Walker M, Fry L (1992) Is epidermal cell proliferation in psoriatic skin grafts on nude mice driven by T‐cell derived cytokines? Brit J Dermatol 126:105–110
Li J, Li X, Zhang Y, Zhou X, Yang H, Chen X, Wang Y, Wei Y, Chen L, Hu H et al (2010) Gene therapy for psoriasis in the K14‐VEGF transgenic mouse model by topical transdermal delivery of interleukin‐4 using ultradeformable cationic liposome. J Gene Med 12:481–490
van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 182:5836–5845
Guilloteau K, Paris I, Pedretti N, Boniface K, Juchaux F, Huguier V, Guillet G, Bernard FX, Lecron JC, Morel F (2010) Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1 alpha, and TNF-alpha recapitulates some features of psoriasis. J Immunol 184:5263–5270
Banno T, Gazel A, Blumenberg M (2004) Effects of tumor necrosis factor-α (TNFα) in epidermal keratinocytes revealed using global transcriptional profiling. J Biol Chem 279:32633–32642
Boniface K, Diveu C, Morel F, Pedretti N, Froger J, Ravon E, Garcia M, Venereau E, Preisser L, Guignouard E (2007) Oncostatin M secreted by skin infiltrating T lymphocytes is a potent keratinocyte activator involved in skin inflammation. J Immunol 178:4615–4622
Mee JB, Johnson CM, Morar N, Burslem F, Groves RW (2007) The psoriatic transcriptome closely resembles that induced by interleukin-1 in cultured keratinocytes: dominance of innate immune responses in psoriasis. Am J Pathol 171:32–42
Nograles K, Zaba L, Guttman‐Yassky E, Fuentes‐Duculan J, Suárez‐Fariñas M, Cardinale I, Khatcherian A, Gonzalez J, Pierson K, White T (2008) Th17 cytokines interleukin (IL)‐17 and IL‐22 modulate distinct inflammatory and keratinocyte‐response pathways. Brit J Dermatol 159:1092–1102
Schoop VM, Mirancea N, Fusenig NE (1999) Epidermal organization and differentiation of HaCaT keratinocytes in organotypic coculture with human dermal fibroblasts. J Invest Dermatol 112:343–353
Boniface K, Lecron JC, Bernard FX, Dagregorio G, Guillet G, Nau F, Morel F (2005) Keratinocytes as targets for interleukin-10-related cytokines: a putative role in the pathogenesis of psoriasis. Eur Cytokine Netw 16:309–319
Spinks E, Fenwick G (1990) The determination of glycyrrhizin in selected UK liquorice products. Food Addit Contam 7:769–778
Andres RM, Montesinos MC, Navalon P, Paya M, Terencio MC (2013) NF-kappa B and STAT3 inhibition as a therapeutic strategy in psoriasis: in vitro and in vivo effects of BTH. J Invest Dermatol 133:2362–2371
Maggiolini M, Statti G, Vivacqua A, Gabriele S, Rago V, Loizzo M, Menichini F, Amdò S (2002) Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. J Steroid Biochem 82:315–322
Chen G, Zhu L, Liu Y, Zhou Q, Chen H, Yang J (2009) Isoliquiritigenin, a flavonoid from licorice, plays a dual role in regulating gastrointestinal motility in vitro and in vivo. Phytother Res 23:498–506
Hsia SM, Shieh TM, Shih YH (2012) Effects of isoliquiritigenin (ISL) on VEGF secretion in human breast cancer cell line MDA-MB-231. Cancer Res 72:1991–1991
Wang KL, Hsia SM, Chan CJ, Chang FY, Huang CY, Bau DT, Wang PS (2013) Inhibitory effects of isoliquiritigenin on the migration and invasion of human breast cancer cells. Expert Opin Ther Tar 17:337–349
Jung SK, Lee MH, Kim JE, Singh P, Lee SY, Jeong CH, Lim TG, Chen H, Chi YI, Kundu JK (2014) Isoliquiritigenin induces apoptosis and inhibits xenograft tumor growth of human lung cancer cells by targeting both wild type and L858R/T790M mutant EGFR. J Biol Chem 289:35839–35848
Di Cesare A, Di Meglio P, Nestle FO (2009) The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol 129:1339–1350
Pietrzak AT, Zalewska A, Chodorowska G, Krasowska D, Michalak-Stoma A, Nockowski P, Osemlak P, Paszkowski T, Roliński JM (2008) Cytokines and anticytokines in psoriasis. Clin Chim Acta 394:7–21
Perera GK, Di Meglio P, Nestle FO (2012) Psoriasis. Annu Rev Pathol-Mech Dis 7:385–422
Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PF (2013) NF-κB: an essential transcription factor in psoriasis. J Dermatol Sci 69:89–94
Acknowledgments
We thank Dr. Xiu Teng for the human keratinocyte cell line HaCaT and helpful suggestions in the vitro studies, Congcong Shen for excellent discussions, Xuewen Jin for real-time quantitative PCR analysis and expert suggestions, Weiyong Xu and Juan He for excellent technical assistance in HE staining, Fanghua Li for immunohistochemistry analysis, and Min Wu and John Yun-Chung Chen for the revision of the manuscript.
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No potential conflicts of interest were disclosed.
Grant support
This study was supported by National Science and Technology Major Projects (No. 2012ZX09103-301-045).
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Yangping Wu and Xiangzheng Chen contributed equally to this work.
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Wu, Y., Chen, X., Ge, X. et al. Isoliquiritigenin prevents the progression of psoriasis-like symptoms by inhibiting NF-κB and proinflammatory cytokines. J Mol Med 94, 195–206 (2016). https://doi.org/10.1007/s00109-015-1338-3
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DOI: https://doi.org/10.1007/s00109-015-1338-3