Regulatory Effect on Skin Differentiation by Mevastatin in Psoriasis Model Using TNF-α and IL-17 Induced HaCaT Cells

다국어 초록 (Multilingual Abstract)

Mevastatin (HMG-CoA reductase inhibitor) isolated from Penicillium citrinum is known to the first statin that inhibitor of cholesterol synthesis. Recently, several clinical reports of other statins suggest its role on reducing the severity of psoriasis, but the available evidence on cellular/molecular level of mevastatin is unclear. Thus, this study was to determine the molecular/cellular mechanism of mevastatin using TNF-α/IL-17A stimulated HaCaT cells. First, the safety and effectiveness of mevastatin were confirmed through the comparative experiment of five statin derivatives. Mevastatin decreased mRNA levels of cytokines (IL-1α/β, IL-6, and IL-8), chemokine (CC motif) ligand 20 (CCL20), and keratin proteins (Keratin 5/14/6/ 16) known to be overexpressed in psoriasis. In addition, mevastatin significantly reduced phosphorylation of NF- κB, MAPKs and STAT3 in TNF-α/IL-17 signaling pathway. Moreover, mevastatin specifically suppressed keratin 5/14 proteins expressed in the keratinocyte differentiation process of the basal layer and keratin 6A/16 overexpressed in patients with psoriasis. These results imply that mevastatin not only can inhibit psoriasis-induced inflammatory cytokines and chemokines, but also can suppress psoriasisrelated keratin proteins.

참고문헌 (Reference)

1 Sun, W, "′Psoriasis 1′ reduces psoriasis-like skin inflammation by inhibiting the VDR-mediated nuclear NFκB and STAT signaling pathways" 18 : 2733-2743, 2018

2 Akhyani, M, "The lipid profile in psoriasis: a controlled study" 21 : 1330-1332, 2007

3 Eckert, R. L, "The epidermal keratinocyte as a model for the study of gene regulation and cell differentiation" 77 : 397-424, 1997

4 Stossel, T. P, "The discovery of statins" 134 : 903-905, 2008

5 Harper, E. G, "Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis" 129 : 2175-2183, 2009

6 Istvan, E. S, "Structural mechanism for statin inhibition of HMG-CoA reductase" 292 : 1160-1164, 2001

7 Kim, T. G, "Statins inhibit chemotactic interaction between CCL20 and CCR6 in vitro: possible relevance to psoriasis treatment" 20 : 855-857, 2011

8 Zhao, Y, "Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita" 131 : 1045-1052, 2011

9 Uyanik, B. S, "Serum lipids and apolipoproteins in patients with psoriasis. Clin" 40 : 65-68, 2002

10 Seishima, M., "Serum lipid and apolipoprotein levels in patients with psoriasis" 130 : 738-742, 1994

11 Arican, O, "Serum levels of TNF-α, IFN-γ, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity" 2005 : 273-279, 2005

12 SuleymanPiskin, "Serum Lipid Levels in Psoriasis" 연세대학교의과대학 44 (44): 24-26, 2003

13 Chen, S, "Responses of multipotent retinal stem cells to IL-1β, IL-18, or IL-17" 2015 : 369312-, 2015

14 Hirata, T, "Recruitment of CCR6-expressing Th17 cells by CCL 20 secreted from IL-1β-, TNF-α-, and IL-17A-stimulated endometriotic stromal cells" 151 : 5468-5476, 2010

15 Res, P. C. M, "Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis" 5 : e14108-, 2010

16 Paramio, J. M, "Modulation of cell proliferation by cytokeratins K10 and K16" 19 : 3086-3094, 1999

17 Nagy, P, "Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2" 115 : 4251-4262, 2002

18 Zhang, X, "Keratin 6, 16 and 17-critical barrier alarmin molecules in skin wounds and psoriasis" 8 : 807-, 2019

19 Shi, X, "IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms" 131 : 2401-2408, 2011

20 Henness, S, "IL-17A augments TNF-α-induced IL-6expression in airway smooth muscle by enhancing mRNA stability" 114 : 958-964, 2004

21 Iyoda, M, "IL-17A and IL-17F stimulate chemokines via MAPK pathways (ERK1/2 and p38 but not JNK) in mouse cultured mesangial cells: synergy with TNF-αand IL-1β" 298 : F779-F787, 2009

22 Weber, C, "HMGCoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia" 30 : 1212-1217, 1997

23 Jiang, C. K, "Epidermal growth factor and transforming growth factor alpha specifically induce the activation- and hyperproliferation-associated keratins 6 and 16" 90 : 6786-6790, 1993

24 Chen, Y. J, "ERK2-mediated C-terminal serine phosphorylation of p300 is vital to the regulation of epidermal growth factor-induced keratin 16gene expression" 282 : 27215-27228, 2007

25 Rocha-Pereira, P, "Dislipidemia and oxidative stress in mild and in severe psoriasis as a risk for cardiovascular disease" 303 : 33-39, 2001

26 Ohta, K, "Differential regulation by IFN-γ on TNF-α-induced chemokine expression in synovial fibroblasts from temporomandibular joint" 16 : 6850-6857, 2017

27 Zamvil, S. S, "Cholesterol-lowering statins possess anti-inflammatory activity that might be useful for treatment of MS" 59 : 970-971, 2002

28 Ringerike, T, "Cholesterol is important in control of EGF receptor kinase activity but EGF receptors are not concentrated in caveolae" 115 : 1331-1340, 2002

29 Udommethaporn, S, "Assessment of anti-TNF-α activities in keratinocytes expressing inducible TNF-α: a novel tool for anti-TNF-α drug screening" 11 : e0159151-, 2016

30 최다희, "Anti‑inflammation activity of brazilin in TNF‑α induced human psoriasis dermatitis skin model" 한국응용생명화학회 62 (62): 1-9, 2019

31 Wongwaisayawan, H, "Antikeratin 14 monoclonal antibody staining in psoriasis and seborrhoeic keratosis: immunofluorescence and two colour FACS studies" 283 : 405-410, 1991

32 Grine, L, "An inflammatory triangle in psoriasis: TNF, type I IFNs and IL17" 26 : 25-33, 2015