The inhibitory effects of Geranium thunbergii on interferon-γ- and LPS-induced inflammatory responses are mediated by Nrf2 activation

Choi,Hee-Jin; Choi,Hee-Jung; Park,Mi-Ju; Lee,Ji-Yeon; Jeong,Seung-Il; Lee,Seongoo; Kim,Kyun  Ha; Joo,Myungsoo; Jeong,Han-Sol; Kim,Jai-Eun; Ha,Ki-Tae

doi:10.3892/ijmm.2015.2128

The inhibitory effects of Geranium thunbergii on interferon-γ- and LPS-induced inflammatory responses are mediated by Nrf2 activation

Authors:
- Hee-Jin Choi
- Hee-Jung Choi
- Mi-Ju Park
- Ji-Yeon Lee
- Seung-Il Jeong
- Seongoo Lee
- Kyun Ha Kim
- Myungsoo Joo
- Han-Sol Jeong
- Jai-Eun Kim
- Ki-Tae Ha
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Affiliations: Department of Pathology, College of Korean Medicine, Dongguk University, Siksa-dong, Ilsan, Gyeonggi-do, Republic of Korea, Department of Korean Medical Science, School of Korean Medicine and Korean Medicine Research Center for Healthy Aging, Pusan National University, Mulgeum-eup, Yangsan, Gyeongsangnam-do, Republic of Korea, Jeonju Biomaterials Institute, Jeonju, Republic of Korea, Department of Korean Pathology, College of Korean Medicine, Sangji University, Wonju, Gangwon, Republic of Korea
Published online on: March 6, 2015 https://doi.org/10.3892/ijmm.2015.2128
Pages: 1237-1245
Copyright: © Choi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Geranium thunbergii Sieb. et Zucc. (GT; which belongs to the Geraniaceae family) has been used as a traditional medicine in East Asia for the treatment of inflammatory diseases, including arthritis and diarrhea. However, the underlying mechanisms of the anti-inflammatory effects of GT remain poorly understood. In the present study, we examined the mechanisms responsible for the anti-inflammatory activity of GT in macrophages. The results revealed that GT significantly inhibited the lipopolysaccharide (LPS)- and interferon-γ (IFN-γ)-induced expression of pro-inflammatory genes, such as inducible nitric oxide synthase, tumor necrosis factor-α and interleukin-1β, as shown by RT-PCR. However, the inhibitory effects of GT on LPS- and IFN-γ-induced inflammation were associated with an enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) activity, but not with the suppression of nuclear factor (NF)-κB activity, as shown by western blot analysis. In addition, in bone marrow-derived macrophages (BMDM) isolated from Nrf2 knockout mice, GT did not exert any inhibitory effect on the LPS- and IFN-γ-induced inflammation. Taken together, our findings indicate that the anti-inflammatory effects of GT may be associated with the activation of Nrf2, an anti-inflammatory transcription factor.

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1	Reuter S, Gupta SC, Chaturvedi MM and Aggarwal BB: Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med. 49:1603–1616. 2010. View Article : Google Scholar : PubMed/NCBI
2	Nathan C and Ding A: Nonresolving inflammation. Cell. 140:871–882. 2010. View Article : Google Scholar : PubMed/NCBI
3	Laskin DL, Sunil VR, Gardner CR and Laskin JD: Macrophages and tissue injury: Agents of defense or destruction? Annu Rev Pharmacol Toxicol. 51:267–288. 2011. View Article : Google Scholar
4	Davignon JL, Hayder M, Baron M, Boyer JF, Constantin A, Apparailly F, Poupot R and Cantagrel A: Targeting monocytes/macrophages in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 52:590–598. 2013. View Article : Google Scholar
5	Alam J, Stewart D, Touchard C, Boinapally S, Choi AM and Cook JL: Nrf2, a Cap‘n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem. 274:26071–26078. 1999. View Article : Google Scholar : PubMed/NCBI
6	Baird L and Dinkova-Kostova AT: The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol. 85:241–272. 2011. View Article : Google Scholar : PubMed/NCBI
7	Maicas N, Ferrándiz ML, Brines R, Ibáñez L, Cuadrado A, Koenders MI, van den Berg WB and Alcaraz MJ: Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid Redox Signal. 15:889–901. 2011. View Article : Google Scholar : PubMed/NCBI
8	Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS and Kong AN: Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res. 66:11580–11584. 2006. View Article : Google Scholar : PubMed/NCBI
9	Chan K and Kan YW: Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci USA. 96:12731–12736. 1999. View Article : Google Scholar : PubMed/NCBI
10	Kaplan M, Mutlu EA, Benson M, Fields JZ, Banan A and Keshavarzian A: Use of herbal preparations in the treatment of oxidant-mediated inflammatory disorders. Complement Ther Med. 15:207–216. 2007. View Article : Google Scholar : PubMed/NCBI
11	Lee SE, Jeong SI, Yang H, Jeong SH, Jang YP, Park CS, Kim J and Park YS: Extract of Salvia miltiorrhiza (Danshen) induces Nrf2-mediated heme oxygenase-1 expression as a cytoprotective action in RAW 264.7 macrophages. J Ethnopharmacol. 139:541–548. 2012. View Article : Google Scholar
12	Lee JA, Lee MY, Shin IS, Seo CS, Ha H and Shin HK: Anti-inflammatory effects of Amomum compactum on RAW 264.7 cells via induction of heme oxygenase-1. Arch Pharm Res. 35:739–746. 2012. View Article : Google Scholar : PubMed/NCBI
13	Choi JY, Kwun MJ, Kim KH, et al: Protective Effect of the fruit hull of Gleditsia sinensis on LPS-induced acute lung injury is associated with Nrf2 activation. Evid Based Complement Alternat Med. 2012:9747132012. View Article : Google Scholar : PubMed/NCBI
14	Han CW, Kwun MJ, Kim KH, Choi JY, Oh SR, Ahn KS, Lee JH and Joo M: Ethanol extract of Alismatis Rhizoma reduces acute lung inflammation by suppressing NF-κB and activating Nrf2. J Ethnopharmacol. 146:402–410. 2013. View Article : Google Scholar : PubMed/NCBI
15	Ju MS, Jeong HU, Kim HG, et al: Anti-nociceptive and anti-inflammatory effects of Geranii Herba. Kor J Herbol. 25:97–101. 2010.
16	Liu QH, Jeong JE, Choi EJ, Moon YH and Woo ER: A new furofuran lignan from Geranium thunbergii Sieb. et Zucc. Arch Pharm Res. 29:1109–1113. 2006. View Article : Google Scholar
17	Hiramatsu N, Xiufen W, Takechi R, Itoh Y, Mamo J and Pal S: Antimutagenicity of Japanese traditional herbs, gennoshoko, yomogi, senburi and iwa-tobacco. Biofactors. 22:123–125. 2004. View Article : Google Scholar
18	Xiufen W, Hiramatsu N and Matsubara M: The antioxidative activity of traditional Japanese herbs. Biofactors. 21:281–284. 2004. View Article : Google Scholar
19	Sung YY, Yoon T, Yang WK, Kim SJ and Kim HK: Anti-obesity effects of Geranium thunbergii extract via improvement of lipid metabolism in high-fat diet-induced obese mice. Mol Med Rep. 4:1107–1113. 2011.PubMed/NCBI
20	Liu QH and Woo ER: Inhibitory activity of IL-6 production by flavonoids and phenolic compounds. Nat Prod Sci. 14:1–5. 2008.
21	Okuda T, Mori K and Murakami R: Constituents of Geranium thunbergii Sieb. et Zucc. VI. Difference of tannin activity caused by structural differences. (2). Colorimetry with methylene blue (author’s transl). Yakugaku Zasshi. 97:1273–1278. 1977.In Japanese. PubMed/NCBI
22	Okuda T, Yoshida T and Mori K: Consitutents of Geranium thunbergii Sieb. et Zucc. II. Ellagitannins. (1) (author’s transl). Yakugaku Zasshi. 95:1462–1466. 1975.In Japanese. PubMed/NCBI
23	Harborne JB, Baxter H and Moss GP: Phytochemical Dictionary: A Handbook of Bioactive Compounds from Plants. Taylor and Francis; London, Philadelphia: 1999
24	Barthwal MK, Anzinger JJ, Xu Q, Bohnacker T, Wymann MP and Kruth HS: Fluid-phase pinocytosis of native low density lipoprotein promotes murine M-CSF differentiated macrophage foam cell formation. PLoS One. 8:e580542013. View Article : Google Scholar : PubMed/NCBI
25	Lyu JH, Lee GS, Kim KH, et al: ent-kaur-16-en-19-oic Acid, isolated from the roots of Aralia continentalis, induces activation of Nrf2. J Ethnopharmacol. 137:1442–1449. 2011. View Article : Google Scholar : PubMed/NCBI
26	Okuda T, Mori K and Ishino M: Constituents of Geranium thunbergii Sieg. et Zucc. VIII. Transformations of geraniin upon decoction (author’s transl). Yakugaku Zasshi. 99:505–509. 1979.In Japanese. PubMed/NCBI
27	Johnson JA, Johnson DA, Kraft AD, Calkins MJ, Jakel RJ, Vargas MR and Chen PC: The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration. Ann NY Acad Sci. 1147:61–69. 2008. View Article : Google Scholar : PubMed/NCBI
28	Wakabayashi N, Slocum SL, Skoko JJ, Shin S and Kensler TW: When NRF2 talks, who’s listening? Antioxid Redox Signal. 13:1649–1663. 2010. View Article : Google Scholar : PubMed/NCBI
29	Drexler SK, Kong PL, Wales J and Foxwell BM: Cell signalling in macrophages, the principal innate immune effector cells of rheumatoid arthritis. Arthritis Res Ther. 10:2162008. View Article : Google Scholar : PubMed/NCBI
30	Schroder K, Sweet MJ and Hume DA: Signal integration between IFNgamma and TLR signalling pathways in macrophages. Immunobiology. 211:511–524. 2006. View Article : Google Scholar : PubMed/NCBI
31	Korhonen R, Lahti A, Kankaanranta H and Moilanen E: Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy. 4:471–479. 2005. View Article : Google Scholar : PubMed/NCBI
32	Gupta SC, Sundaram C, Reuter S and Aggarwal BB: Inhibiting NF-κB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta. 1799:775–787. 2010. View Article : Google Scholar : PubMed/NCBI
33	Tornatore L, Thotakura AK, Bennett J, Moretti M and Franzoso G: The nuclear factor-kappa B signaling pathway: Integrating metabolism with inflammation. Trends Cell Biol. 22:557–566. 2012. View Article : Google Scholar : PubMed/NCBI
34	Spehlmann ME and Eckmann L: Nuclear factor-kappa B in intestinal protection and destruction. Curr Opin Gastroenterol. 25:92–99. 2009. View Article : Google Scholar : PubMed/NCBI
35	Saito H: Toxico-pharmacological perspective of the Nrf2-Keap1 defense system against oxidative stress in kidney diseases. Biochem Pharmacol. 85:865–872. 2013. View Article : Google Scholar : PubMed/NCBI
36	Kim J, Cha YN and Surh YJ: A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res. 690:12–23. 2010. View Article : Google Scholar
37	Jin W, Wang H, Yan W, Xu L, Wang X, Zhao X, Yang X, Chen G and Ji Y: Disruption of Nrf2 enhances upregulation of nuclear factor-kappaB activity, proinflammatory cytokines, and inter-cellular adhesion molecule-1 in the brain after traumatic brain injury. Mediators Inflamm. 2008:7251742008. View Article : Google Scholar
38	Turpaev KT: Keap1-Nrf2 signaling pathway: Mechanisms of regulation and role in protection of cells against toxicity caused by xenobiotics and electrophiles. Biochem Mosc. 78:111–126. 2013. View Article : Google Scholar
39	Jeong WS, Kim IW, Hu R and Kong AN: Modulatory properties of various natural chemopreventive agents on the activation of NF-kappaB signaling pathway. Pharm Res. 21:661–670. 2004. View Article : Google Scholar : PubMed/NCBI
40	Márquez N, Sancho R, Macho A, Calzado MA, Fiebich BL and Muñoz E: Caffeic acid phenethyl ester inhibits T-cell activation by targeting both nuclear factor of activated T-cells and NF-kappaB transcription factors. J Pharmacol Exp Ther. 308:993–1001. 2004. View Article : Google Scholar
41	Xu YX, Pindolia KR, Janakiraman N, Chapman RA and Gautam SC: Curcumin inhibits IL1 alpha and TNF-alpha induction of AP-1 and NF-κB DNA-binding activity in bone marrow stromal cells. Hematopathol Mol Hematol. 11:49–62. 1997–1998.
42	Moreira AJ, Fraga C, Alonso M, Collado PS, Zetller C, Marroni C, Marroni N and González-Gallego J: Quercetin prevents oxidative stress and NF-kappaB activation in gastric mucosa of portal hypertensive rats. Biochem Pharmacol. 68:1939–1946. 2004. View Article : Google Scholar : PubMed/NCBI
43	Xu C, Shen G, Chen C, Gélinas C and Kong AN: Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene. 24:4486–4495. 2005. View Article : Google Scholar : PubMed/NCBI
44	Manandhar S, You A, Lee ES, Kim JA and Kwak MK: Activation of the Nrf2-antioxidant system by a novel cyclooxygenase-2 inhibitor furan-2-yl-3-pyridin-2-yl-propenone: Implication in anti-inflammatory function by Nrf2 activator. J Pharm Pharmacol. 60:879–887. 2008. View Article : Google Scholar : PubMed/NCBI
45	Li B, Abdalrahman A, Lai Y, Janicki JS, Ward KW, Meyer CJ, Wang XL, Tang D and Cui T: Dihydro-CDDO-trifluoroethyl amide suppresses inflammatory responses in macrophages via activation of Nrf2. Biochem Biophys Res Commun. 444:555–561. 2014. View Article : Google Scholar : PubMed/NCBI