Anti-inflammatory effects of Morus alba Linne bark on the activation of toll-like receptors and imiquimod-induced ear edema in mice

Umeyama L., Hardianti B., Kasahara S., Dibwe D.F., Awale S., Yokoyama S., Hayakawa Y.

Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan; Sekolah Tinggi Ilmu Farmasi Makassar, Perintis Kemerdekaan Street Km 13.7, Makassar, 90242, Indonesia; Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan


Abstract

Background: Morus alba L. bark has been widely used in traditional medicine for treating several inflammatory diseases, such as hypertension, diabetes mellitus and coughing; however, the molecular mechanisms underlying its anti-inflammatory effects are not well understood. Methods: We examined the effects of an extract of Morus alba L. bark (MabE) on Toll-like receptor (TLR) ligand-induced activation of RAW264.7 macrophages using a luciferase reporter assay and immunoassays. For the in vivo experiment, we used an imiquimod-induced ear edema model to examine the anti-inflammatory effects of MabE. Results: MabE inhibited the TLR ligand-induced activation of NF-κB in RAW264.7 cells without affecting their viability. Consistent with the inhibition of NF-κB activation, MabE also inhibited the production of IL-6 and IL-1β from TLR ligand-treated RAW264.7 cells. In vivo MabE treatment inhibited the ear swelling of IMQ-treated mice, in addition to the mRNA expression of IL-17A, IL-1β and COX-2. The increases in splenic γδT cells in IMQ-treated mice and the production of IL-17A from splenocytes were significantly inhibited by MabE treatment. Conclusion: Our study suggests that the anti-inflammatory effects of MabE on the activation of the macrophage cell line RAW246.7 by TLRs and IMQ-induced ear edema are through the inhibition of NF-κB activation and IL-17A-producing γδT cells, respectively. © 2021, The Author(s).

Inflammation; Innate immunity; Morus alba L. bark; Psoriasis; Toll-like receptor


Journal

BMC Complementary Medicine and Therapies

Publisher: BioMed Central Ltd

Volume 21, Issue 1, Art No 115, Page – , Page Count


Journal Link: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85104063012&doi=10.1186%2fs12906-021-03291-5&partnerID=40&md5=4b701e2ab3e8e6f1fa8acfae6e03b13c

doi: 10.1186/s12906-021-03291-5

Issn: 26627671

Type: All Open Access, Gold, Green


References

Medzhitov, R., Origin and physiological roles of inflammation (2008) Nature, 454 (7203), pp. 428-435; Chung, H.Y., Cesari, M., Anton, S., Marzetti, E., Giovannini, S., Seo, A.Y., Carter, C., Leeuwenburgh, C., Molecular inflammation: underpinnings of aging and age-related diseases (2009) Ageing Res Rev, 8 (1), pp. 18-30; Hotamisligil, G.S., Inflammation, metaflammation and immunometabolic disorders (2017) Nature, 542 (7640), pp. 177-185; Lai, K.S.P., Liu, C.S., Rau, A., Lanctot, K.L., Kohler, C.A., Pakosh, M., Carvalho, A.F., Herrmann, N., Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies (2017) J Neurol Neurosurg Psychiatry, 88 (10), pp. 876-882; Gerondakis, S., Grumont, R., Gugasyan, R., Wong, L., Isomura, I., Ho, W., Banerjee, A., Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models (2006) Oncogene, 25 (51), pp. 6781-6799; Diakos, C.I., Charles, K.A., McMillan, D.C., Clarke, S.J., Cancer-related inflammation and treatment effectiveness (2014) Lancet Oncol, 15 (11), pp. e493-e503; Ramakrishnan, S.K., Zhang, H., Ma, X., Jung, I., Schwartz, A.J., Triner, D., Devenport, S.N., Shah, Y.M., Intestinal non-canonical NFkappaB signaling shapes the local and systemic immune response (2019) Nat Commun, 10 (1), p. 660; Patel, S., Danger-associated molecular patterns (DAMPs): the derivatives and triggers of inflammation (2018) Curr Allergy Asthma Rep, 18 (11), p. 63; Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.M., Hoffmann, J.A., The dorsoventral regulatory gene cassette spatzle/toll/cactus controls the potent antifungal response in Drosophila adults (1996) Cell, 86 (6), pp. 973-983; Medzhitov, R., Preston-Hurlburt, P., Janeway, C.A., Jr., A human homologue of the Drosophila toll protein signals activation of adaptive immunity (1997) Nature, 388 (6640), pp. 394-397; Baccala, R., Hoebe, K., Kono, D.H., Beutler, B., Theofilopoulos, A.N., TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity (2007) Nat Med, 13 (5), pp. 543-551; Akira, S., Takeda, K., Kaisho, T., Toll-like receptors: critical proteins linking innate and acquired immunity (2001) Nat Immunol, 2 (8), pp. 675-680; Kawai, T., Akira, S., Toll-like receptors and their crosstalk with other innate receptors in infection and immunity (2011) Immunity, 34 (5), pp. 637-650; Iwakura, Y., Nakae, S., Saijo, S., Ishigame, H., The roles of IL-17A in inflammatory immune responses and host defense against pathogens (2008) Immunol Rev, 226 (1), pp. 57-79; Papotto, P.H., Ribot, J.C., Silva-Santos, B., IL-17(+) gammadelta T cells as kick-starters of inflammation (2017) Nat Immunol, 18 (6), pp. 604-611; Wang, L., Yi, T., Zhang, W., Pardoll, D.M., Yu, H., IL-17 enhances tumor development in carcinogen-induced skin cancer (2010) Cancer Res, 70 (24), pp. 10112-10120; Onishi, R.M., Gaffen, S.L., Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease (2010) Immunology, 129 (3), pp. 311-321; Kimura, Y., Nagai, N., Tsunekawa, N., Sato-Matsushita, M., Yoshimoto, T., Cua, D.J., Iwakura, Y., Hayakawa, Y., IL-17A-producing CD30(+) Vdelta1 T cells drive inflammation-induced cancer progression (2016) Cancer Sci, 107 (9), pp. 1206-1214; Lee, H.J., Ryu, J., Park, S.H., Woo, E.R., Kim, A.R., Lee, S.K., Kim, Y.S., Lee, C.J., Effects of Morus alba L. and Natural Products Including Morusin on In Vivo Secretion and In Vitro Production of Airway MUC5AC Mucin (2014) Tuberc Respir Dis (Seoul), 77 (2), pp. 65-72; Jin, S.E., Ha, H., Shin, H.K., Seo, C.S., Anti-Allergic and Anti-Inflammatory Effects of Kuwanon G and Morusin on MC/9 Mast Cells and HaCaT Keratinocytes (2019) Molecules, 24 (2), p. 265; Hardianti, B., Umeyama, L., Li, F., Yokoyama, S., Hayakawa, Y., Identification of anti-inflammatory compounds from Morus alba Linne by targeting NF-κB pathway (2020) Mol Med Rep, 22 (6), pp. 5385-5391; Nwet Win, N., Hardianti, B., Kasahara, S., Ngwe, H., Hayakawa, Y., Morita, H., Anti-inflammatory activities of isopimara-8(14),-15-diene diterpenoids and mode of action of kaempulchraols P and Q from Kaempferia pulchra rhizomes (2020) Bioorg Med Chem Lett, 30 (2), p. 126841; van der Fits, L., Mourits, S., Voerman, J.S., Kant, M., Boon, L., Laman, J.D., Cornelissen, F., Prens, E.P., Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis (2009) J Immunol, 182 (9), pp. 5836-5845; Murray, P.J., Wynn, T.A., Protective and pathogenic functions of macrophage subsets (2011) Nat Rev Immunol, 11 (11), pp. 723-737; Roach, J.C., Glusman, G., Rowen, L., Kaur, A., Purcell, M.K., Smith, K.D., Hood, L.E., Aderem, A., The evolution of vertebrate toll-like receptors (2005) Proc Natl Acad Sci U S A, 102 (27), pp. 9577-9582; Barton, G.M., Kagan, J.C., A cell biological view of toll-like receptor function: regulation through compartmentalization (2009) Nat Rev Immunol, 9 (8), pp. 535-542; Cui, J., Chen, Y., Wang, H.Y., Wang, R.F., Mechanisms and pathways of innate immune activation and regulation in health and cancer (2014) Hum Vaccin Immunother, 10 (11), pp. 3270-3285; Hommes, D.W., Peppelenbosch, M.P., van Deventer, S.J., Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets (2003) Gut, 52 (1), pp. 144-151; Kaminska, B., MAPK signalling pathways as molecular targets for anti-inflammatory therapy–from molecular mechanisms to therapeutic benefits (2005) Biochim Biophys Acta, 1754 (1-2), pp. 253-262; Dumitru, C.D., Ceci, J.D., Tsatsanis, C., Kontoyiannis, D., Stamatakis, K., Lin, J.H., Patriotis, C., Tsichlis, P.N., TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway (2000) Cell, 103 (7), pp. 1071-1083; Moos, S., Mohebiany, A.N., Waisman, A., Kurschus, F.C., Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes (2019) J Investig Dermatol, 139 (5), pp. 1110-1117; Isailovic, N., Daigo, K., Mantovani, A., Selmi, C., Interleukin-17 and innate immunity in infections and chronic inflammation (2015) J Autoimmun, 60, pp. 1-11; Xie, X.-J., D, T., Wang, Y., Wang, M.-X., Meng, Y.-J., Lin, Y., Xu, X.-L., Zhao, J.-X., Indirubin ameliorates imiquimod-induced psoriasis-like skin lesions in mice by inhibiting inflammatory responses mediated by IL-17A-producing γδ T cells (2018) Mol Immunol, 101, pp. 386-395; Campbell, J.J., Ebsworth, K., Ertl, L.S., McMahon, J.P., Newland, D., Wang, Y., Liu, S., Zhang, P., IL-17–secreting γδ T cells are completely dependent upon CCR6 for homing to inflamed skin (2017) J Immunol, 199 (9), pp. 3129-3136

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