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Published in: Journal of Natural Medicines 3/2013

01-07-2013 | Original Paper

Modulation of chemokine expression on intestinal epithelial cells by Kampo (traditional Japanese herbal) medicine, Hochuekkito, and its active ingredients

Authors: Michiko Sekiya, Hiroaki Kiyohara, Hiroko Maruyama, Takeshi Yabe, Haruki Yamada

Published in: Journal of Natural Medicines | Issue 3/2013

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Abstract

The intestinal epithelial cells sit at the interface between a lumen and a lamina propria or lymph nodes such as Peyer’s patches, where they play important roles in maintaining intestinal homeostasis through chemokine secretion. This study investigated the effect of Hochuekkito (TJ-41)—a traditional Japanese herbal (Kampo) formula used as a tonic for weakness—on chemokine expression in intestinal epithelial cells in order to explore the mechanism of its modulating effect against mucosal immunity. When cells from the rat normal small intestinal epithelial cell-line IEC-6 were stimulated with TJ-41, mRNA expression of CC chemokine ligand (CCL) 11 (eotaxin), CCL20 (MIP-3α) and CCL25 (TECK) was enhanced. Oral administration of TJ-41 to methotrexate-treated mice enhanced mRNA expression of CCL25 and keratinocyte growth factor in the jejunum with, decreasing mRNA expression of the inflammatory marker tumor necrosis factor (TNF)-α. Although oral administration of TJ-41 did not affect CCL20 mRNA expression in villus epithelium of methotrexate-treated mice, enhancement of CCL20 mRNA expression was observed in Peyer’s patches. Immunohistochemical analysis detected dense staining with anti-CCL20 antibody in the follicle-associated epithelium region of Peyer’s patches in mice administered TJ-41. Analysis of active ingredients indicates that polysaccharide-containing macromolecules in TJ-41 contribute to the enhancement of CCL20 mRNA expression through an intracellular signal cascade via nuclear factor kappa B (NF-κB) activation.
Literature
1.
go back to reference Terasawa K (1993) Kampo. In: Japanese-oriental medicine: insights from clinical cases. Standard McIntyre, Tokyo Terasawa K (1993) Kampo. In: Japanese-oriental medicine: insights from clinical cases. Standard McIntyre, Tokyo
2.
go back to reference Hanawa T (1995) Series of contemporary medicine 20: lesson of clinical practice for Kampo medicine. Kinbara, Tokyo Hanawa T (1995) Series of contemporary medicine 20: lesson of clinical practice for Kampo medicine. Kinbara, Tokyo
3.
go back to reference Kitahara M, lshikawa S (2002) Prevention of infection with MRSA by Hochu-ekki-to in patients with protracted consciousness disorder. Biotherapy 16:261–263 Kitahara M, lshikawa S (2002) Prevention of infection with MRSA by Hochu-ekki-to in patients with protracted consciousness disorder. Biotherapy 16:261–263
4.
go back to reference Fukuti Y (2008) COPD as systemic illness: efficacy of Hochuekkito. Geriatr Med 46:263–266 Fukuti Y (2008) COPD as systemic illness: efficacy of Hochuekkito. Geriatr Med 46:263–266
5.
go back to reference Ohara T, Onda M, Futagawa S, Hiki Y, Iwasaki Y (1993) Clinical evaluation of combined effect of Bu-Zhong-Yi-Qi-Tang (Japanese name, Hochu-Ekki-To) or Ren-Shen-Yang-Rong-Tang (Japanese name, Ninjin-Youei-To) and anti-cancer drug (Tegaful). Jpn Pharmacol Ther 21:4423–4434 Ohara T, Onda M, Futagawa S, Hiki Y, Iwasaki Y (1993) Clinical evaluation of combined effect of Bu-Zhong-Yi-Qi-Tang (Japanese name, Hochu-Ekki-To) or Ren-Shen-Yang-Rong-Tang (Japanese name, Ninjin-Youei-To) and anti-cancer drug (Tegaful). Jpn Pharmacol Ther 21:4423–4434
6.
go back to reference Kiyohara H, Nagai T, Munakata K, Nonaka K, Hanawa T, Kim SJ, Yamada H (2006) Stimulating effect of Japanese herbal (kampo) medicine, Hochuekkito on upper respiratory mucosal immune system. Evid Based Complement Alternat Med 3:459–467PubMedCrossRef Kiyohara H, Nagai T, Munakata K, Nonaka K, Hanawa T, Kim SJ, Yamada H (2006) Stimulating effect of Japanese herbal (kampo) medicine, Hochuekkito on upper respiratory mucosal immune system. Evid Based Complement Alternat Med 3:459–467PubMedCrossRef
7.
go back to reference Matsumoto T, Noguchi M, Hayashi O, Makino K, Yamada H (2010) Hochuekkito, a Kampo (traditional Japanese herbal) medicine, enhances mucosal IgA antibody response in mice immunized with antigen-entrapped biodegradable microparticles. Evid Based Complement Alternat Med 7:69–77PubMedCrossRef Matsumoto T, Noguchi M, Hayashi O, Makino K, Yamada H (2010) Hochuekkito, a Kampo (traditional Japanese herbal) medicine, enhances mucosal IgA antibody response in mice immunized with antigen-entrapped biodegradable microparticles. Evid Based Complement Alternat Med 7:69–77PubMedCrossRef
8.
go back to reference Kiyono H, Fukuyama S (2004) NALT- versus Peyer’s-patch-mediated mucosal immunity. Nat Rev Immunol 4:699–710PubMedCrossRef Kiyono H, Fukuyama S (2004) NALT- versus Peyer’s-patch-mediated mucosal immunity. Nat Rev Immunol 4:699–710PubMedCrossRef
9.
go back to reference Dahan S, Roth-Walter F, Arnaboldi P, Agarwal S, Mayer L (2007) Epithelia: lymphocyte interactions in the gut. Immunol Rev 215:243–253PubMedCrossRef Dahan S, Roth-Walter F, Arnaboldi P, Agarwal S, Mayer L (2007) Epithelia: lymphocyte interactions in the gut. Immunol Rev 215:243–253PubMedCrossRef
10.
go back to reference Zhao X, Sato A, Dela Cruz CS, Linehan M, Luegering A, Kucharzik T, Shirakawa AK, Marquez G, Farber JM, Williams I, Iwasaki A (2003) CCL9 is secreted by the follicle-associated epithelium and recruits dome region Peyer’s patch CD11b+ dendritic cells. J Immunol 171:2797–2803PubMed Zhao X, Sato A, Dela Cruz CS, Linehan M, Luegering A, Kucharzik T, Shirakawa AK, Marquez G, Farber JM, Williams I, Iwasaki A (2003) CCL9 is secreted by the follicle-associated epithelium and recruits dome region Peyer’s patch CD11b+ dendritic cells. J Immunol 171:2797–2803PubMed
11.
go back to reference Hart AL, Ng SC, Mann E, Al-Hassi HO, Bernardo D, Knight SC (2010) Homing of immune cells: role in homeostasis and intestinal inflammation. Inflamm Bowel Dis 16:1969–1977PubMedCrossRef Hart AL, Ng SC, Mann E, Al-Hassi HO, Bernardo D, Knight SC (2010) Homing of immune cells: role in homeostasis and intestinal inflammation. Inflamm Bowel Dis 16:1969–1977PubMedCrossRef
12.
13.
go back to reference Ahrens R, Waddell A, Seidu L, Blanchard C, Carey R, Forbes E, Lampinen M, Wilson T, Cohen E, Stringer K, Ballard E, Munitz A, Xu H, Lee N, Lee JJ, Rothenberg ME, Denson L, Hogan SP (2008) Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis. J Immunol 181:7390–7399PubMed Ahrens R, Waddell A, Seidu L, Blanchard C, Carey R, Forbes E, Lampinen M, Wilson T, Cohen E, Stringer K, Ballard E, Munitz A, Xu H, Lee N, Lee JJ, Rothenberg ME, Denson L, Hogan SP (2008) Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis. J Immunol 181:7390–7399PubMed
14.
go back to reference Ebisawa M, Hase K, Takahashi D, Kitamura H, Knoop KA, Williams IR, Ohno H (2011) CCR6hiCD11c(int) B cells promote M-cell differentiation in Peyer’s patch. Int Immunol 23:261–269PubMedCrossRef Ebisawa M, Hase K, Takahashi D, Kitamura H, Knoop KA, Williams IR, Ohno H (2011) CCR6hiCD11c(int) B cells promote M-cell differentiation in Peyer’s patch. Int Immunol 23:261–269PubMedCrossRef
15.
go back to reference Matsumoto T, Moriya M, Kiyohara H, Tabuchi Y, Yamada H (2010) Hochuekkito, a Kampo (traditional Japanese herbal) medicine, and its polysaccharide portion stimulate G-CSF secretion from intestinal epithelial cells. Evid Based Complement Alternat Med 7:331–340PubMedCrossRef Matsumoto T, Moriya M, Kiyohara H, Tabuchi Y, Yamada H (2010) Hochuekkito, a Kampo (traditional Japanese herbal) medicine, and its polysaccharide portion stimulate G-CSF secretion from intestinal epithelial cells. Evid Based Complement Alternat Med 7:331–340PubMedCrossRef
16.
go back to reference Aida Y, Pabst MJ (1990) Removal of endotoxin from protein solutions by phase separation using Triton X-114. J Immunol Methods 132:191–195PubMedCrossRef Aida Y, Pabst MJ (1990) Removal of endotoxin from protein solutions by phase separation using Triton X-114. J Immunol Methods 132:191–195PubMedCrossRef
17.
go back to reference Kiyohara H, Nonaka K, Sekiya M, Matsumoto T, Nagai T, Tabuchi Y, Yamada H (2011) Polysaccharide-containing macromolecules in a Kampo (traditional Japanese herbal) medicine, Hochuekkito: dual active ingredients for modulation of immune functions on intestinal Peyer’s patches and epithelial cells. Evid Based Complement Alternat Med, Article ID 492691. doi: 10.1093/ecam/nep193 Kiyohara H, Nonaka K, Sekiya M, Matsumoto T, Nagai T, Tabuchi Y, Yamada H (2011) Polysaccharide-containing macromolecules in a Kampo (traditional Japanese herbal) medicine, Hochuekkito: dual active ingredients for modulation of immune functions on intestinal Peyer’s patches and epithelial cells. Evid Based Complement Alternat Med, Article ID 492691. doi: 10.​1093/​ecam/​nep193
18.
go back to reference Zimmerman NP, Vongsa RA, Wendt MK, Dwinell MB (2008) Chemokines and chemokine receptors in mucosal homeostasis at the intestinal epithelial barrier in inflammatory bowel disease. Inflamm Bowel Dis 14:1000–1011PubMedCrossRef Zimmerman NP, Vongsa RA, Wendt MK, Dwinell MB (2008) Chemokines and chemokine receptors in mucosal homeostasis at the intestinal epithelial barrier in inflammatory bowel disease. Inflamm Bowel Dis 14:1000–1011PubMedCrossRef
19.
go back to reference Boukhettala N, Leblond J, Claeyssens S, Faure M, Le Pessot F, Bôle-Feysot C, Hassan A, Mettraux C, Vuichoud J, Lavoinne A, Breuillé D, Déchelotte P, Coëffier M (2009) Methotrexate induces intestinal mucositis and alters gut protein metabolism independently of reduced food intake. Am J Physiol Endocrinol Metab 296:E182–E190PubMedCrossRef Boukhettala N, Leblond J, Claeyssens S, Faure M, Le Pessot F, Bôle-Feysot C, Hassan A, Mettraux C, Vuichoud J, Lavoinne A, Breuillé D, Déchelotte P, Coëffier M (2009) Methotrexate induces intestinal mucositis and alters gut protein metabolism independently of reduced food intake. Am J Physiol Endocrinol Metab 296:E182–E190PubMedCrossRef
20.
go back to reference de Koning BA, van Dieren JM, Lindenbergh-Kortleve DJ, van der Sluis M, Matsumoto T, Yamaguchi K, Einerhand AW, Samsom JN, Pieters R, Nieuwenhuis EE (2006) Contributions of mucosal immune cells to methotrexate-induced mucositis. Int Immunol 18:941–949PubMedCrossRef de Koning BA, van Dieren JM, Lindenbergh-Kortleve DJ, van der Sluis M, Matsumoto T, Yamaguchi K, Einerhand AW, Samsom JN, Pieters R, Nieuwenhuis EE (2006) Contributions of mucosal immune cells to methotrexate-induced mucositis. Int Immunol 18:941–949PubMedCrossRef
21.
go back to reference Onai N, Kitabatake M, Zhang YY, Ishikawa H, Ishikawa S, Matsushima K (2002) Pivotal role of CCL25 (TECK)-CCR9 in the formation of gut cryptopatches and consequent appearance of intestinal intraepithelial T lymphocytes. Int Immunol 14:687–694PubMedCrossRef Onai N, Kitabatake M, Zhang YY, Ishikawa H, Ishikawa S, Matsushima K (2002) Pivotal role of CCL25 (TECK)-CCR9 in the formation of gut cryptopatches and consequent appearance of intestinal intraepithelial T lymphocytes. Int Immunol 14:687–694PubMedCrossRef
22.
go back to reference Boismenu R, Havran WL (1994) Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266:1253–1255PubMedCrossRef Boismenu R, Havran WL (1994) Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266:1253–1255PubMedCrossRef
23.
go back to reference Williams IR (2006) CCR6 and CCL20: partners in intestinal immunity and lymphorganogenesis. Ann N Y Acad Sci 1072:52–61PubMedCrossRef Williams IR (2006) CCR6 and CCL20: partners in intestinal immunity and lymphorganogenesis. Ann N Y Acad Sci 1072:52–61PubMedCrossRef
24.
go back to reference Hase K, Murakami T, Takatsu H, Shimaoka T, Iimura M, Hamura K, Kawano K, Ohshima S, Chihara R, Itoh K, Yonehara S, Ohno H (2006) The membrane-bound chemokine CXCL16 expressed on follicle-associated epithelium and M cells mediates lympho-epithelial interaction in GALT. J Immunol 176:43–51PubMed Hase K, Murakami T, Takatsu H, Shimaoka T, Iimura M, Hamura K, Kawano K, Ohshima S, Chihara R, Itoh K, Yonehara S, Ohno H (2006) The membrane-bound chemokine CXCL16 expressed on follicle-associated epithelium and M cells mediates lympho-epithelial interaction in GALT. J Immunol 176:43–51PubMed
25.
go back to reference Cook DN, Prosser DM, Forster R, Zhang J, Kuklin NA, Abbondanzo SJ, Niu XD, Chen SC, Manfra DJ, Wiekowski MT, Sullivan LM, Smith SR, Greenberg HB, Narula SK, Lipp M, Lira SA (2000) CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 12:495–503PubMedCrossRef Cook DN, Prosser DM, Forster R, Zhang J, Kuklin NA, Abbondanzo SJ, Niu XD, Chen SC, Manfra DJ, Wiekowski MT, Sullivan LM, Smith SR, Greenberg HB, Narula SK, Lipp M, Lira SA (2000) CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 12:495–503PubMedCrossRef
26.
go back to reference Sirard JC, Didierlaurent A, Cayet D, Sierro F, Rumbo M (2009) Toll-like receptor 5- and lymphotoxin beta receptor-dependent epithelial Ccl20 expression involves the same NF-kappa B binding site but distinct NF-kappa B pathways and dynamics. Biochim Biophys Acta 1789:386–394PubMedCrossRef Sirard JC, Didierlaurent A, Cayet D, Sierro F, Rumbo M (2009) Toll-like receptor 5- and lymphotoxin beta receptor-dependent epithelial Ccl20 expression involves the same NF-kappa B binding site but distinct NF-kappa B pathways and dynamics. Biochim Biophys Acta 1789:386–394PubMedCrossRef
27.
go back to reference Bogunovic M, Davé SH, Tilstra JS, Chang DT, Harpaz N, Xiong H, Mayer LF, Plevy SE (2007) Enteroendocrine cells express functional Toll-like receptors. Am J Physiol Gastrointest Liver Physiol 292:G1770–G1783PubMedCrossRef Bogunovic M, Davé SH, Tilstra JS, Chang DT, Harpaz N, Xiong H, Mayer LF, Plevy SE (2007) Enteroendocrine cells express functional Toll-like receptors. Am J Physiol Gastrointest Liver Physiol 292:G1770–G1783PubMedCrossRef
28.
go back to reference Saegusa S, Totsuka M, Kaminogawa S, Hosoi T (2004) Candida albicans and Saccharomyces cerevisiae induce interleukin-8 production from intestinal epithelial-like Caco-2 cells in the presence of butyric acid. FEMS Immunol Med Microbiol 41:227–235PubMedCrossRef Saegusa S, Totsuka M, Kaminogawa S, Hosoi T (2004) Candida albicans and Saccharomyces cerevisiae induce interleukin-8 production from intestinal epithelial-like Caco-2 cells in the presence of butyric acid. FEMS Immunol Med Microbiol 41:227–235PubMedCrossRef
29.
go back to reference de Kivit S, Kraneveld AD, Garssen J, Willemsen LE (2011) Glycan recognition at the interface of the intestinal immune system: target for immune modulation via dietary components. Eur J Pharmacol 668(Suppl 1):S124–S132PubMedCrossRef de Kivit S, Kraneveld AD, Garssen J, Willemsen LE (2011) Glycan recognition at the interface of the intestinal immune system: target for immune modulation via dietary components. Eur J Pharmacol 668(Suppl 1):S124–S132PubMedCrossRef
30.
go back to reference Wrackmeyer U, Hansen GH, Seya T, Danielsen EM (2006) Intelectin: a novel lipid raft-associated protein in the enterocyte brush border. Biochemistry 45:9188–9197PubMedCrossRef Wrackmeyer U, Hansen GH, Seya T, Danielsen EM (2006) Intelectin: a novel lipid raft-associated protein in the enterocyte brush border. Biochemistry 45:9188–9197PubMedCrossRef
31.
go back to reference Skjoedt MO, Palarasah Y, Rasmussen K, Vitved L, Salomonsen J, Kliem A, Hansen S, Koch C, Skjodt K (2010) Two mannose-binding lectin homologues and an MBL-associated serine protease are expressed in the gut epithelia of the urochordates species Ciona intestinalis. Dev Comp Immunol 34:59–68PubMedCrossRef Skjoedt MO, Palarasah Y, Rasmussen K, Vitved L, Salomonsen J, Kliem A, Hansen S, Koch C, Skjodt K (2010) Two mannose-binding lectin homologues and an MBL-associated serine protease are expressed in the gut epithelia of the urochordates species Ciona intestinalis. Dev Comp Immunol 34:59–68PubMedCrossRef
Metadata
Title
Modulation of chemokine expression on intestinal epithelial cells by Kampo (traditional Japanese herbal) medicine, Hochuekkito, and its active ingredients
Authors
Michiko Sekiya
Hiroaki Kiyohara
Hiroko Maruyama
Takeshi Yabe
Haruki Yamada
Publication date
01-07-2013
Publisher
Springer Japan
Published in
Journal of Natural Medicines / Issue 3/2013
Print ISSN: 1340-3443
Electronic ISSN: 1861-0293
DOI
https://doi.org/10.1007/s11418-012-0724-1

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