Rhododendron album Blume extract inhibits TNF-α/IFN-γ-induced chemokine production via blockade of NF-κB and JAK/STAT activation in human epidermal keratinocytes

Park,Ji‑Won; Lee,Han‑Sol; Lim,Yourim; Paik,Jin‑Hyub; Kwon,Ok‑Kyoung; Kim,Jung‑Hee; Paryanto,Imam; Yunianto,Prasetyawan; Choi,Sangho; Oh,Sei‑Ryang; Ahn,Kyung‑Seop

doi:10.3892/ijmm.2018.3556

Rhododendron album Blume extract inhibits TNF-α/IFN-γ-induced chemokine production via blockade of NF-κB and JAK/STAT activation in human epidermal keratinocytes

Authors:
- Ji‑Won Park
- Han‑Sol Lee
- Yourim Lim
- Jin‑Hyub Paik
- Ok‑Kyoung Kwon
- Jung‑Hee Kim
- Imam Paryanto
- Prasetyawan Yunianto
- Sangho Choi
- Sei‑Ryang Oh
- Kyung‑Seop Ahn
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Affiliations: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungbuk 28116, Republic of Korea, International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea, Center for Pharmaceutical and Medical Technology, Kawasan Puspiptek Serpong, LAPTIAB, Tangerang, Banten 15314, Indonesia
Published online on: March 9, 2018 https://doi.org/10.3892/ijmm.2018.3556
Pages: 3642-3652

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Abstract

Rhododendron album Blume (RA) has traditionally been used as an herbal medicine and is considered to have anti‑inflammatory properties. It is a well‑known medicine for treatment of allergic or atopic diseases. In the present study, the biological effects of an RA methanol extract (RAME) on inflammation were investigated in tumor necrosis factor‑α (TNF‑α)/interferon‑γ (IFN‑γ)‑stimulated human keratinocytes. The present study aimed to investigate the potential mechanisms by which RAME inhibited TNF‑α/IFN‑γ‑induced expression of chemokines [thymus‑ and activation-regulated chemokine (TARC) and macrophage‑derived chemokine (MDC)] and cytokines [interleukin (IL)‑6 and IL‑8] through the nuclear factor‑κB (NF‑κB) pathway in human keratinocytes. The effects of RAME treatment on cell viability were investigated in TNF‑α/IFN‑γ‑stimulated HaCaT cells. The expression of TARC, MDC, IL‑6 and IL‑8 was assessed using reverse transcription‑quantitative polymerase chain reaction analysis or ELISA, and its effect on the inhibitory mitogen-activated protein kinase pathway was also studied using western blot analysis. TNF‑α/IFN‑γ induced the expression of IL‑6, IL‑8, TARC and MDC in a dose‑dependent manner through NF‑κB and Janus kinase/signal transducers and activators of transcription (JAK/STAT) activation. Notably, treatment with RAME significantly suppressed TNF-α/IFN-γ-induced expression of IL‑6, IL‑8, TARC, and MDC. In addition, RAME treatment inhibited the activation of NF‑κB and the JAK/STAT pathway in TNF‑α/IFN‑γ‑induced HaCaT cells. These results suggest that RAME decreases the production of chemokines and pro‑inflammatory cytokines by suppressing the NF‑κB and the JAK/STAT pathways. Consequently, RAME may potentially be used for treatment of atopic dermatitis.

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1	Brandt EB and Sivaprasad U: Th2 cytokines and atopic dermatitis. J Clin Cell Immunol. 2:pii. 1102011. View Article : Google Scholar : PubMed/NCBI
2	Abramovits W: Atopic dermatitis. J Am Acad Dermatol. 53(1 Suppl 1): S86–S93. 2005. View Article : Google Scholar : PubMed/NCBI
3	Portugal-Cohen M, Horev L, Ruffer C, Schlippe G, Voss W, Ma'or Z, Oron M, Soroka Y, Frušić-Zlotkin M, Milner Y and Kohen R: Non-invasive skin biomarkers quantification of psoriasis and atopic dermatitis: Cytokines, antioxidants and psoriatic skin auto-fluorescence. Biomed Pharmacother. 66:293–299. 2012. View Article : Google Scholar : PubMed/NCBI
4	Hoffjan S and Stemmler S: On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis. Br J Dermatol. 157:441–449. 2007. View Article : Google Scholar : PubMed/NCBI
5	Nakatsuji T, Chen TH, Two AM, Chun KA, Narala S, Geha RS, Hata TR and Gallo RL: Staphylococcus aureus exploits epidermal barrier defects in atopic dermatitis to trigger cytokine expression. J Invest Dermatol. 136:2192–2200. 2016. View Article : Google Scholar : PubMed/NCBI
6	Leung DY, Boguniewicz M, Howell MD, Nomura I and Hamid QA: New insights into atopic dermatitis. J Clin Invest. 113:651–657. 2004. View Article : Google Scholar : PubMed/NCBI
7	Yang IJ, Lee DU and Shin HM: Inhibitory effect of valencene on the development of atopic dermatitis-like skin lesions in nc/nga mice. Evid Based Complement Alternat Med. 2016:93708932016. View Article : Google Scholar : PubMed/NCBI
8	Zlotnik A and Yoshie O: Chemokines: A new classification system and their role in immunity. Immunity. 12:121–127. 2000. View Article : Google Scholar : PubMed/NCBI
9	Kang GJ, Han SC, Yi EJ, Kang HK and Yoo ES: The inhibitory effect of premature citrus unshiu extract on atopic dermatitis in vitro and in vivo. Toxicol Res. 27:173–180. 2011. View Article : Google Scholar
10	Vestergaard C, Yoneyama H, Murai M, Nakamura K, Tamaki K, Terashima Y, Imai T, Yoshie O, Irimura T, Mizutani H and Matsushima K: Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions. J Clin Invest. 104:1097–1105. 1999. View Article : Google Scholar : PubMed/NCBI
11	Horikawa T, Nakayama T, Hikita I, Yamada H, Fujisawa R, Bito T, Harada S, Fukunaga A, Chantry D, Gray PW, et al: IFN-gamma-inducible expression of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in epidermal keratinocytes and their roles in atopic dermatitis. Int Immunol. 14:767–773. 2002. View Article : Google Scholar : PubMed/NCBI
12	Sebastiani S, Albanesi C, De PO, Puddu P, Cavani A and Girolomoni G: The role of chemokines in allergic contact dermatitis. Arch Dermatol Res. 293:552–559. 2002. View Article : Google Scholar : PubMed/NCBI
13	Shimada Y, Takehara K and Sato S: Both Th2 and Th1 chemokines (TARC/CCL17, MDC/CCL22, and Mig/CXCL9) are elevated in sera from patients with atopic dermatitis. J Dermatol Sci. 34:201–208. 2004. View Article : Google Scholar : PubMed/NCBI
14	Kimura M, Haisa M, Uetsuka H, Takaoka M, Ohkawa T, Kawashima R, Yamatsuji T, Gunduz M, Kaneda Y, Tanaka N and Naomoto Y: TNF combined with IFN-alpha accelerates NF-kappaB-mediated apoptosis through enhancement of Fas expression in colon cancer cells. Cell Death Differ. 10:718–728. 2003. View Article : Google Scholar : PubMed/NCBI
15	Rath PC: Relationship between constitutive nuclear factor-kappaB (NF-kappaB) and inhibitor kappaB-alpha (IkappaB-alpha) in an interferon-alpha-sensitive human Burkitt lymphoma cell line. Biochim Biophys Acta. 1741:253–263. 2005. View Article : Google Scholar : PubMed/NCBI
16	Baeuerle PA and Baichwal VR: NF-kappa B as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv Immunol. 65:111–137. 1997. View Article : Google Scholar : PubMed/NCBI
17	Ortis F, Pirot P, Naamane N, Kreins AY, Rasschaert J, Moore F, Théâtre E, Verhaeghe C, Magnusson NE, Chariot A, et al: Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells. Diabetologia. 51:1213–1225. 2008. View Article : Google Scholar : PubMed/NCBI
18	Cao ZH, Yin WD, Zheng QY, Feng SL, Xu GL and Zhang KQ: Caspase-3 is involved in IFN-γ- and TNF-α-mediated MIN6 cells apoptosis via NF-κB/Bcl-2 pathway. Cell Biochem Biophys. 67:1239–1248. 2013. View Article : Google Scholar
19	Ali S, Nisar M, Qaisar M, Khan A and Khan AA: Evaluation of the cytotoxic potential of a new pentacyclic triterpene from Rhododendron arboreum stem bark. Pharm Biol. 55:1927–1930. 2017. View Article : Google Scholar : PubMed/NCBI
20	Li FR, Yu FX, Yao ST, Si YH, Zhang W and Gao LL: Hyperin extracted from Manchurian rhododendron leaf induces apoptosis in human endometrial cancer cells through a mitochondrial pathway. Asian Pac J Cancer Prev. 13:3653–3656. 2012. View Article : Google Scholar : PubMed/NCBI
21	Liu YL, Lin LC, Tung YT, Ho ST, Chen YL, Lin CC and Wu JH: Rhododendron oldhamii leaf extract improves fatty liver syndrome by increasing lipid oxidation and decreasing the lipogenesis pathway in mice. Int J Med Sci. 14:862–870. 2017. View Article : Google Scholar :
22	Park JW, Kwon OK, Kim JH, Oh SR, Kim JH, Paik JH, Marwoto B, Widjhati R, Juniarti F, Irawan D and Ahn KS: Rhododendron album Blume inhibits iNOS and COX-2 expression in LPS-stimulated RAW264.7 cells through the downregulation of NF- κB signaling. Int J Mol Med. 35:987–994. 2015. View Article : Google Scholar : PubMed/NCBI
23	Lee JW, Park JW, Kwon OK, Lee HJ, Jeong HG, Kim JH, Oh SR and Ahn KS: NPS2143 Inhibits MUC5AC and proinflammatory mediators in cigarette smoke extract (CSE)-stimulated human airway epithelial cells. Inflammation. 40:184–194. 2017. View Article : Google Scholar
24	Ko JW, Park JW, Shin NR, Kim JH, Cho YK, Shin DH, Kim JC, Lee IC, Oh SR, Ahn KS and Shin IS: Copper oxide nanoparticle induces inflammatory response and mucus production via MAPK signaling in human bronchial epithelial cells. Environ Toxicol Pharmacol. 43:21–26. 2016. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
26	Shibata S, Maeda S, Kondo N, Chimura N, Inoue A and Fukata T: Identification of the signaling pathway of TNF-α-induced CCL17/TARC transcription in a canine keratinocyte cell line. Vet Immunol Immunopathol. 139:90–98. 2011. View Article : Google Scholar
27	Cho BO, Che DN, Yin HH, Shin JY and Jang SI: Diospyros lotus leaf and grapefruit stem extract synergistically ameliorate atopic dermatitis-like skin lesion in mice by suppressing infiltration of mast cells in skin lesions. Biomed Pharmacother. 89:819–826. 2017. View Article : Google Scholar : PubMed/NCBI
28	Homey B, Steinhoff M, Ruzicka T and Leung DY: Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol. 118:178–189. 2006. View Article : Google Scholar : PubMed/NCBI
29	Nedoszytko B, Sokołowska-Wojdyło M, Ruckemann-Dziurdzińska K, Roszkiewicz J and Nowicki RJ: Chemokines and cytokines network in the pathogenesis of the inflammatory skin diseases: Atopic dermatitis, psoriasis and skin mastocytosis. Postepy Dermatol Alergol. 31:84–91. 2014. View Article : Google Scholar : PubMed/NCBI
30	Giuliani C, Napolitano G, Bucci I, Montani V and Monaco F: Nf-κB transcription factor: Role in the pathogenesis of inflammatory, autoimmune, and neoplastic diseases and therapy implications. Clin Ter. 152:249–253. 2001.In Italian. PubMed/NCBI
31	Chen Y, Xian Y, Lai Z, Loo S, Chan WY and Lin ZX: Anti-inflammatory and anti-allergic effects and underlying mechanisms of Huang-Lian-Jie-Du extract: Implication for atopic dermatitis treatment. J Ethnopharmacol. 185:41–52. 2016. View Article : Google Scholar : PubMed/NCBI
32	Park JW, Kim YJ, Shin IS, Kwon OK, Hong JM, Shin NR, Oh SR, Ha UH, Kim JH and Ahn KS: Type III secretion system of Pseudomonas aeruginosa affects matrix metalloproteinase 12 (MMP-12) and MMP-13 Expression via nuclear factor κB signaling in human carcinoma epithelial cells and a pneumonia mouse model. J Infect Dis. 214:962–969. 2016. View Article : Google Scholar : PubMed/NCBI
33	Park JW, Shin IS, Ha UH, Oh SR, Kim JH and Ahn KS: Pathophysiological changes induced by Pseudomonas aeruginosa infection are involved in MMP-12 and MMP-13 upregulation in human carcinoma epithelial cells and a pneumonia mouse model. Infect Immun. 83:4791–4799. 2015. View Article : Google Scholar : PubMed/NCBI
34	Kim HH, Kim SW, Kim DS, Oh HM, Rho MC and Kim SH: Vigna angularis inhibits mast cell-mediated allergic inflammation. Int J Mol Med. 32:736–742. 2013. View Article : Google Scholar : PubMed/NCBI
35	Park JW, Lee IC, Shin NR, Jeon CM, Kwon OK, Ko JW, Kim JC, Oh SR, Shin IS and Ahn KS: Copper oxide nanoparticles aggravate airway inflammation and mucus production in asthmatic mice via MAPK signaling. Nanotoxicology. 10:445–452. 2016. View Article : Google Scholar
36	Jeong YH, Oh YC, Cho WK, Lee B and Ma JY: Anti-inflammatory effects of melandrii herba ethanol extract via inhibition of NF-κB and MAPK signaling pathways and induction of HO-1 in RAW 264.7 cells and mouse primary macrophages. Molecules. 21:pii. E8182016. View Article : Google Scholar
37	Zheng G, Shen Z, Chen H, Liu J, Jiang K, Fan L, Jia L and Shao J: Metapristone suppresses non-small cell lung cancer proliferation and metastasis via modulating RAS/RAF/MEK/MAPK signaling pathway. Biomed Pharmacother. 90:437–445. 2017. View Article : Google Scholar : PubMed/NCBI
38	Zhao S, Sun Y, Li X, Wang J, Yan L, Zhang Z, Wang D, Dai J, He J and Wang S: Scutellarin inhibits RANKL-mediated osteoclastogenesis and titanium particle-induced osteolysis via suppression of NF-κB and MAPK signaling pathway. Int Immunopharmacol. 40:458–465. 2016. View Article : Google Scholar : PubMed/NCBI
39	Park JW, Kwon OK, Yuniato P, Marwoto B, Lee J, Oh SR, Kim JH and Ahn KS: Amelioration of an LPS-induced inflammatory response using a methanolic extract of Lagerstroemia ovalifolia to suppress the activation of NF-κB in RAW264.7 macrophages. Int J Mol Med. 38:482–490. 2016. View Article : Google Scholar : PubMed/NCBI