Secretome Hypoxia Mesenchymal Stem Cells Inhibited Ultraviolet Radiation by Inhibiting Interleukin-6 through Nuclear Factor-Kappa Beta Pathway in Hyperpigmentation Animal Models

Yunita Ika Mayasari; Prasetyowati Subchan; Agung Putra; Chodijah Chodijah; Atina Hussana; Titiek Sumarawati; Nur Dina Amalina; Rizky Candra Satria Irawan

doi:10.3889/oamjms.2023.11222

Authors

Yunita Ika Mayasari Department of Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia
Prasetyowati Subchan Department of Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia
Agung Putra Department of Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia; Stem Cell and Cancer Research, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia; Department of Pathological Anatomy, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia https://orcid.org/0000-0003-4261-9437
Chodijah Chodijah Department of Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia
Atina Hussana Department of Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia
Titiek Sumarawati Department of Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia
Nur Dina Amalina Stem Cell and Cancer Research, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia; Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Negeri Semarang, Semarang, Indonesia https://orcid.org/0000-0002-6314-3661
Rizky Candra Satria Irawan Stem Cell and Cancer Research, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2023.11222

Keywords:

Secretome hypoxic mesenchymal stem cells, p65, p50, Interleukin-6, Hyperpigmentation

Abstract

UVB radiation is the main factor causing hyperpigmentation. Secretome hypoxic mesenchymal stem cells (S-HMSCs) contain bioactive soluble molecules such as growth factors and anti-inflammatory cytokines that can prevent melanin synthesis and induce collagen formation. However, the role of S-HMSCSs on IL-6, p50, and p65 gene expression in hyperpigmentation is still unclear. This study aimed to determine the effect of administration of S-HMSCSs gel on the expression of IL-6, p50, and p65 in a hyperpigmented rat skin model induced by UVB light exposure. Twenty-five male Wistar rats of hyperpigmented were created as an animal model under exposed to UVB 6 times in 14 days at 302 nm with a MED of 390 mJ/cm2. The animal was randomly assigned into five groups consisting of two treatment groups (treated by S-HMSCs at a 100µL as T1 and 200µL as T2 on bases gel) for 14 days, control groups (UVB-irradiation), sham (negative control), and base gel groups. On the 14th day, IL-6, p50, and p65 were terminated and analyzed using qRT-PCR. Statistical analysis will perform using one way ANOVA followed with post hoc LSD test. Analysis of IL-6 (8.59± 3.32), p50 (4.35±2.27), and p65 (4.09±1.82) gene expression in the treatment group decreased along with the increase in the concentration of S-MSCs compared to the control group. In conclusion, the administration of S-HMSCs gel is expected to affect the speed of decreasing the hyperpigmentation process significantly.

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References

Moon HR, Jung JM, Kim SY, Song Y, Chang SE. TGF-β3 suppresses melanogenesis in human melanocytes cocultured with UV-irradiated neighboring cells and human skin. J Dermatol Sci. 2020;99(2):100-8. https://doi.org/10.1016/j.jdermsci.2020.06.007 PMid:32620316 DOI: https://doi.org/10.1016/j.jdermsci.2020.06.007

Alam MB, Bajpai VK, Lee JI, Zhao P, Byeon JH, Ra JS, et al. Inhibition of melanogenesis by jineol from Scolopendra subspinipes mutilans via MAP-Kinase mediated MITF downregulation and the proteasomal degradation of tyrosinase. Sci Rep. 2017;7:45858. https://doi.org/10.1038/srep45858 PMid:28393917 DOI: https://doi.org/10.1038/srep45858

Jablonski NG, Chaplin G. Human skin pigmentation as an adaptation to UV radiation. Proc Natl Acad Sci U S A. 2010;107 Suppl 2:8962-8. https://doi.org/10.1073/pnas.0914628107 PMid:20445093 DOI: https://doi.org/10.1073/pnas.0914628107

Baliña LM, Graupe K. The treatment of Melasma 20% Azelaic acid versus 4% hydroquinone cream. Int J Dermatol. 1991;30(12):893-5. https://doi.org/10.1111/j.1365-4362.1991.tb04362.x PMid:1816137 DOI: https://doi.org/10.1111/j.1365-4362.1991.tb04362.x

Sarkar R, Bhalla M, Kanwar AJ. A comparative study of 20% azelaic acid cream monotherapy versus a sequential therapy in the treatment of melasma in dark-skinned patients. Dermatology. 2002;205(2–3):249-54. https://doi.org/10.1159/000065851 PMid:12399672 DOI: https://doi.org/10.1159/000065851

Yokawa K, Kagenishi T, Baluška F. UV-B induced generation of reactive oxygen species promotes formation of BFA-induced compartments in cells of Arabidopsis root apices. Front Plant Sci. 2016;6:1162. https://doi.org/10.3389/fpls.2015.01162 PMid:26793199 DOI: https://doi.org/10.3389/fpls.2015.01162

Lingappan K. NF-κB in oxidative stress. Curr Opin Toxicol. 2018;7:81-6. https://doi.org/10.1016/j.cotox.2017.11.002 PMid:29862377 DOI: https://doi.org/10.1016/j.cotox.2017.11.002

Bashir MM, Sharma MR, Werth VP. UVB and proinflammatory cytokines synergistically activate TNF-α production in keratinocytes through enhanced gene transcription. J Invest Dermatol. 2009;129(4):994-1001. https://doi.org/10.1038/jid.2008.332 PMid:19005488 DOI: https://doi.org/10.1038/jid.2008.332

Su CM, Wang L, Yoo D. Activation of NF-κB and induction of proinflammatory cytokine expressions mediated by ORF7a protein of SARS-CoV-2. Sci Rep. 2021;11(1):13464. https://doi.org/10.1038/s41598-021-92941-2 PMid:34188167 DOI: https://doi.org/10.1038/s41598-021-92941-2

Wan S, Liu Y, Shi J, Fan D, Li B. Anti-photoaging and anti-inflammatory effects of ginsenoside Rk3 during exposure to UV irradiation. Front Pharmacol. 2021;12:716248. https://doi.org/10.3389/fphar.2021.716248 PMid:34671254 DOI: https://doi.org/10.3389/fphar.2021.716248

Hwang IS, Kim JE, Choi SI, Lee HR, Lee YJ, Jang MJ, et al. UV radiation-induced skin aging in hairless mice is effectively prevented by oral intake of sea buckthorn (Hippophae rhamnoides L.) fruit blend for 6 weeks through MMP suppression and increase of SOD activity. Int J Mol Med. 2012;30(2):392-400. https://doi.org/10.3892/ijmm.2012.1011 PMid:22641502 DOI: https://doi.org/10.3892/ijmm.2012.1011

Su VY, Lin CS, Hung SC, Yang KY. Mesenchymal stem cell-conditioned medium induces neutrophil apoptosis associated with inhibition of the NF-κb pathway in endotoxin-induced acute lung injury. Int J Mol Sci. 2019;20(9):2208. https://doi.org/10.3390/ijms20092208 PMid:31060326 DOI: https://doi.org/10.3390/ijms20092208

Trisnadi S, Muhar AM, Putra A, Kustiyah AR. Hypoxia-preconditioned mesenchymal stem cells attenuate peritoneal adhesion through TGF-β _inhibition. Univers Med. 2020;39(2):97. DOI: https://doi.org/10.18051/UnivMed.2020.v39.97-104

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7. https://doi.org/10.1080/14653240600855905 PMid:16923606 DOI: https://doi.org/10.1080/14653240600855905

Lv FJ, Tuan RS, Cheung KM, Leung VY. Concise review: The surface markers and identity of human mesenchymal stem cells. Stem Cells. 2014;32(6):1408-19. https://doi.org/.1002/stem.1681 PMid:24578244 DOI: https://doi.org/10.1002/stem.1681

Kim DS, Park SH, Park KC. Transforming growth factor-β1 decreases melanin synthesis via delayed extracellular signal-regulated kinase activation. Int J Biochem Cell Biol. 2004;36(8):1482-91. https://doi.org/10.1016/j.biocel.2003.10.023 PMid:15147727 DOI: https://doi.org/10.1016/j.biocel.2003.10.023

Murakami M, Matsuzaki F, Funaba M. Regulation of melanin synthesis by the TGF-β family in B16 melanoma cells. Mol Biol Rep. 2009;36(6):1247-50. https://doi.org/10.1007/s11033-008-9304-6 PMid:18600473 DOI: https://doi.org/10.1007/s11033-008-9304-6

Wellbrock C, Arozarena I. Microphthalmia-associated transcription factor in melanoma development and MAP-kinase pathway targeted therapy. Pigment Cell Melanoma Res. 2015;28(4):390-406. https://doi.org/10.1111/pcmr.12370 PMid:25818589 DOI: https://doi.org/10.1111/pcmr.12370

You YJ, Wu PY, Liu YJ, Hou CW, Wu CS, Wen KC, et al. Sesamol inhibited ultraviolet radiation-induced hyperpigmentation and damage in C57BL/6 mouse skin. Antioxidants. 2019;8(7):207. https://doi.org/10.3390/antiox8070207 PMid:31284438 DOI: https://doi.org/10.3390/antiox8070207

Sungkar T, Putra A, Lindarto D, Sembiring RJ. Intravenous umbilical cord-derived mesenchymal stem cells transplantation regulates hyaluronic acid and interleukin-10 secretion producing low-grade liver fibrosis in experimental rat. Med Arch. 2020;74(3):177-82. https://doi.org/10.5455/medarh.2020.74.177-182 PMid:32801431 DOI: https://doi.org/10.5455/medarh.2020.74.177-182

Putra A, Ridwan FB, Putridewi AI, Kustiyah AR, Wirastuti K, Sadyah NA, et al. The role of tnf-α induced mscs on suppressive inflammation by increasing tgf-β _and il-10. Open Access Maced J Med Sci. 2018;6(10):1779-83. https://doi.org/10.3889/oamjms.2018.404 PMid:30455748 DOI: https://doi.org/10.3889/oamjms.2018.404

Putra A, Alif I, Nazar MA, Prasetio A, Satria Irawan RC, Amalina D, et al. IL-6 and IL-8 suppression by bacteria-adhered mesenchymal stem cells co-cultured with PBMCs under TNF-α exposure. 1st Jenderal Soedirman International Medical Conference: SciTePress; 2021. p. 311-7. DOI: https://doi.org/10.5220/0010491903110317

Restimulia L, Ilyas S, Munir D, Putra A, Madiadipoera T, Farhat F, Sembiring RJ, Ichwan M, Amalina ND, Alif I. The CD4+CD25+FoxP3+ Regulatory T Cells Regulated by MSCs Suppress Plasma Cells in a Mouse Model of Allergic Rhinitis. Med Arch. 2021 Aug;75(4):256-261. https://doi.org/10.5455/ medarh.2021.75.256-261. PMid: 34759444 DOI: https://doi.org/10.5455/medarh.2021.75.256-261

Restimulia L, Ilyas S, Munir D, Putra A, Madiadipoera T, Farhat F, et al. Rats’ umbilical-cord mesenchymal stem cells ameliorate mast cells and Hsp70 on ovalbumin-induced allergic rhinitis rats. Med Glas. 2022;19(1):52-9. https://doi.org/10.17392/1421-21 PMid:35048629

Darlan DM, Munir D, Putra A, Alif I, Amalina ND, Jusuf NK, et al. Revealing the decrease of indoleamine 2,3-dioxygenase as a major constituent for B cells survival post-mesenchymal stem cells co-cultured with peripheral blood mononuclear cell (PBMC) of systemic lupus erythematosus (SLE) patients. Med Glas. 2022;19(1):12-8. https://doi.org/10.17392/1414-21 PMid:35048623

Prajoko YW, Putra A, Dirja BT, Muhar AM, Amalina ND. The ameliorating effects of MSCs in controlling Treg-mediated B-Cell depletion by indoleamine 2, 3-dioxygenase induction in PBMC of SLE patients. Open Access Maced J Med Sci. 2022;10:6-11. DOI: https://doi.org/10.3889/oamjms.2022.7487

Sunarto H, Trisnadi S, Putra A, Sa’dyah NA, Tjipta A, Chodidjah C. The role of hypoxic mesenchymal stem cells conditioned medium in increasing vascular endothelial growth factors (VEGF) levels and collagen synthesis to accelerate wound healing. Indones J Cancer Chemoprevention. 2020;11(3):134. DOI: https://doi.org/10.14499/indonesianjcanchemoprev11iss3pp134-143

Drawina P, Putra A, Nasihun T, Prajoko YW, Dirja BT, Amalina ND. Increased serial levels of platelet-derived growth factor using hypoxic mesenchymal stem cell-conditioned medium to promote closure acceleration in a full-thickness wound. Indones J Biotechnol. 2022;27(1):36. DOI: https://doi.org/10.22146/ijbiotech.64021

Halliday GM. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis. Mutat Res. 2005;571(1-2):107-20. https://doi.org/10.1016/j.mrfmmm.2004.09.013 PMid:15748642 DOI: https://doi.org/10.1016/j.mrfmmm.2004.09.013

Pandel R, Poljšak B, Godic A, Dahmane R. Skin photoaging and the role of antioxidants in its prevention. ISRN Dermatol. 2013;2013:930164. https://doi.org/10.1155/2013/930164 PMid:24159392 DOI: https://doi.org/10.1155/2013/930164

Ansary TM, Hossain MR, Kamiya K, Komine M, Ohtsuki M. Inflammatory molecules associated with ultraviolet radiation-mediated skin aging. Int J Mol Sci. 2021;22(8):3974. https://doi.org/10.3390/ijms22083974 PMid:33921444 DOI: https://doi.org/10.3390/ijms22083974

Sayama K, Yuki K, Sugata K, Fukagawa S, Yamamoto T, Ikeda S, et al. Carbon dioxide inhibits UVB-induced inflammatory response by activating the proton-sensing receptor, GPR65, in human keratinocytes. Sci Rep. 2021;11(1):379. https://doi.org/10.1038/s41598-020-79519-0 PMid:33431967 DOI: https://doi.org/10.1038/s41598-020-79519-0

Ja Choi Y, Mi Moon K, Wung Chung K, Won Jeong J, Park D, Hyun Kim D, et al. The underlying mechanism of proinflammatory NF-κB activation by the mTORC2/Akt/IKKα pathway during skin aging. Oncotarget. 2016;7(33):52685-94. https://doi.org/.18632/oncotarget.10943 PMid:27486771 DOI: https://doi.org/10.18632/oncotarget.10943

Tanaka K, Asamitsu K, Uranishi H, Iddamalgoda A, Ito K, Kojima H, et al. Protecting skin photoaging by NF-B inhibitor. Curr Drug Metab. 2010;11(5):431-5. https://doi.org/10.2174/138920010791526051 PMid:20540695 DOI: https://doi.org/10.2174/138920010791526051

Takeuchi H, Mano Y, Terasaka S, Sakurai T, Furuya A, Urano H, et al. Usefulness of rat skin as a substitute for human skin in the in vitro skin permeation study. Exp Anim. 2011;60(4):373-84. https://doi.org/10.1538/expanim.60.373 PMid:21791877 DOI: https://doi.org/10.1538/expanim.60.373

Duteil L, Cardot-Leccia N, Queille-Roussel C, Maubert Y, Harmelin Y, Boukari F, et al. Differences in visible light-induced pigmentation according to wavelengths: A clinical and histological study in comparison with UVB exposure. Pigment Cell Melanoma Res. 2014;27(5):822-6. https://doi.org/10.1111/pcmr.12273 PMid:24888214 DOI: https://doi.org/10.1111/pcmr.12273

Hamra NF, Putra A, Tjipta A, Amalina ND, Nasihun T. Hypoxia mesenchymal stem cells accelerate wound closure improvement by controlling α-smooth muscle actin expression in the full-thickness animal model. Open Access Maced J Med Sci. 2021;9:35-41. DOI: https://doi.org/10.3889/oamjms.2021.5537

Muhar AM, Putra A, Warli SM, Munir D. Hypoxia-mesenchymal stem cells inhibit intra-peritoneal adhesions formation by upregulation of the il-10 expression. Open Access Maced J Med Sci. 2019;7(23):3937-43. https://doi.org/10.3889/oamjms.2019.713 PMid:32165932 DOI: https://doi.org/10.3889/oamjms.2019.713

Darlan DM, Munir D, Putra A, Jusuf NK. MSCs-released TGFβ1 generate CD4+CD25+Foxp3+ in T-reg cells of human SLE PBMC. J Formosan Med Assoc. 2021;120(1):602-8. https://doi.org/10.1016/j.jfma.2020.06.028 PMid:32718891 DOI: https://doi.org/10.1016/j.jfma.2020.06.028

Putra A, Suwiryo ZH, Muhar AM, Widyatmoko A, Rahmi FL. The role of mesenchymal stem cells in regulating PDGF and VEGF during pancreatic islet cells regeneration in diabetic animal model. Folia Med (Plovdiv). 2021;63(6):875-83. https://doi.org/10.3897/folmed.63.e57636 PMid:35851220 DOI: https://doi.org/10.3897/folmed.63.e57636

Ikhsan R, Putra A, Munir D, Darlan DM, Suntoko B, Retno A. Mesenchymal stem cells induce regulatory T-cell population in human SLE. Bangladesh J Med Sci. 2020;19(04):743-8. DOI: https://doi.org/10.3329/bjms.v19i4.46635

Masyithah Darlan D, Munir D, Karmila Jusuf N, Putra A, Ikhsan R, Alif I. In vitro regulation of IL-6 and TGF-ß by mesenchymal stem cells in systemic lupus erythematosus patients. Med Glas (Zenica). 2020;17(2):408-13. https://doi.org/10.17392/1186-20 PMid:32602296

Driessler F, Venstrom K, Sabat R, Asadullah K, Schottelius AJ. Molecular mechanisms of interleukin-10-mediated inhibition of NF-κB activity: A role for p50. Clin Exp Immunol. 2004;135(1):64-73. https://doi.org/10.1111/j.1365-2249.2004.02342.x PMid:14678266 DOI: https://doi.org/10.1111/j.1365-2249.2004.02342.x

Giridharan S, Srinivasan M. Mechanisms of NF-κB p65 and strategies for therapeutic manipulation. J Inflamm Res. 2018;11:407-19. https://doi.org/10.2147/JIR.S140188 PMid:30464573 DOI: https://doi.org/10.2147/JIR.S140188

Siebenga PS, van Amerongen G, Klaassen ES, de Kam ML, Rissmann R, Groeneveld GJ. The ultraviolet B inflammation model: Postinflammatory hyperpigmentation and validation of a reduced UVB exposure paradigm for inducing hyperalgesia in healthy subjects. Eur J Pain (United Kingdom). 2019;23(5):874-83. https://doi.org/10.1002/ejp.1353 PMid:30597682 DOI: https://doi.org/10.1002/ejp.1353

Collett GP, Campbell FC. Overexpression of p65/RelA potentiates curcumin-induced apoptosis in HCT116 human colon cancer cells. Carcinogenesis. 2006;27(6):1285-91. https://doi.org/10.1093/carcin/bgi368 PMid:16497702 DOI: https://doi.org/10.1093/carcin/bgi368