Abstract
Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.
Similar content being viewed by others
References
Abdou AG, Maraee AH, Sharaf A, Elnaidany NF (2012) Up-regulation of Notch-1 in psoriasis: an immunohistochemical study. Ann Diagn Pathol 16:177–184
Alam MS, Maekawa Y, Kitamura A, Tanigaki K, Yoshimoto T, Kishihara K, Yasutomo K (2010) Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 107:5943–5948
Ambler CA, Watt FM (2010) Adult epidermal Notch activity induces dermal accumulation of T cells and neural crest derivatives through upregulation of jagged 1. Development 137:3569–3579
Amsen D, Antov A, Flavell RA (2009) The different faces of Notch in T-helper-cell differentiation. Nat Rev Immunol 9:116–124
Bartok B, Firestein GS (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233:233–255
Cai Y, Fleming C, Yan J (2012) New insights of T cells in the pathogenesis of psoriasis. Cell Mol Immunol 9:302–309
Cessak G, Kuzawińska O, Burda A, Lis K, Wojnar M, Mirowska-Guzel D, Bałkowiec-Iskra E (2014) TNF inhibitors—mechanisms of action, approved and off-label indications. Pharmacol Rep 66:836–844
Coimbra S, Figueiredo A, Castro E, Rocha-Pereira P, Santos-Silva A (2012) The roles of cells and cytokines in the pathogenesis of psoriasis. Int J Dermatol 51:389–395
Dees C, Tomcik M, Zerr P, Akhmetshina A, Horn A, Palumbo K, Beyer C, Zwerina J, Distler O, Schett G, Distler JH (2011) Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann Rheum Dis 70:1304–1310
Gutcher I, Becher B (2007) APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest 117:1119–1127
Hori K, Sen A, Artavanis-Tsakonas S (2013) Notch signaling at a glance. J Cell Sci 15(126):2135–2140
Jiao Z, Wang W, Ma J, Wang S, Su Z, Xu H (2012) Notch signaling mediates TNF-α-induced IL-6 production in cultured fibroblast-like synoviocytes from rheumatoid arthritis. Clin Dev Immunol 2012:350209
Johnson-Huang LM, Lowes MA, Krueger JG (2012) Putting together the psoriasis puzzle: an update on developing targeted therapies. Dis Model Mech 5:423–433
Keerthivasan S, Suleiman R, Lawlor R, Roderick J, Bates T, Minter L, Anguita J, Juncadella I, Nickoloff BJ, Le Poole IC, Miele L, Osborne BA (2011) Notch signaling regulates mouse and human Th17 differentiation. J Immunol 187:692–701
Kim MY, Jung J, Mo JS, Ann EJ, Ahn JS, Yoon JH, Park HS (2011) The intracellular domain of Jagged-1 interacts with Notch1 intracellular domain and promotes its degradation through Fbw7 E3 ligase. Exp Cell Res 317:2438–2446
LaVoie MJ, Selkoe DJ (2003) The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem 278:34427–34437
Martin DA, Towne JE, Kricorian G, Klekotka P, Gudjonsson JE, Krueger JG, Russell CB (2013) The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol 133:17–26
Michailidis C, Karpouzis A, Kourmouli N, Tripsianis G, Diplas A, Veletza S (2013) Notch2, notch4 gene polymorphisms in psoriasis vulgaris. Eur J Dermatol 23:146–153
Nestle FO, Turka LA, Nickoloff BJ (1994) Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines. J Clin Invest 94:202–209
Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suarez-Farinas M, Cardinale I, Khatcherian A, Gonzalez J, Pierson KC, White TR, Pensabene C, Coats I, Novitskaya I, Lowes MA, Krueger JG (2008) Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol 159:1092–1102
Nowell C, Radtke F (2013) Cutaneous Notch signaling in health and disease. Cold Spring Harb Perspect Med 3:a017772
Park JS, Kim SH, Kim K, Jin CH, Choi KY, Jang J, Choi Y, Gwon AR, Baik SH, Yun UJ, Chae SY, Lee S, Kang YM, Lee KC, Arumugam TV, Mattson MP, Park JH, Jo DG (2015) Inhibition of notch signalling ameliorates experimental inflammatory arthritis. Ann Rheum Dis 74:267–274
Perera GK, Di Meglio P, Nestle FO (2012) Psoriasis. Annu Rev Pathol 7:385–422
Radtke F, MacDonald HR, Tacchini-Cottier F (2013) Regulation of innate and adaptive immunity by Notch. Nat Rev Immunol 13:427–437
Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F, Dotto GP (2001) Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20:3427–3436
Rooney P, Connolly M, Gao W, McCormick J, Biniecka M, Sullivan O, Kirby B, Sweeney C, Molloy E, Markham T, Fearon U, Veale DJ (2014) Notch-1 mediates endothelial cell activation and invasion in psoriasis. Exp Dermatol 23:113–118
Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675
Varghese F, Bukhari AB, Malhotra R, De A (2014) IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS ONE 9:e96801
Xu M, Morishima N, Mizoguchi I, Chiba Y, Fujita K, Kuroda M, Iwakura Y, Cua DJ, Yasutomo K, Mizuguchi J, Yoshimoto T (2011) Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production. Eur J Immunol 41:2828–2839
Yeilding N, Szapary P, Brodmerkel C, Benson J, Plotnick M, Zhou H, Goyal K, Schenkel B, Giles-Komar J, Mascelli MA, Guzzo C (2012) Development of the IL-12/23 antagonist ustekinumab in psoriasis: past, present, and future perspectives-an update. Ann N Y Acad Sci 1263:1–12
Yu S, Liu C, Li L, Tian T, Wang M, Hu Y, Yuan C, Zhang L, Ji C, Ma D (2015) Inactivation of Notch signaling reverses the Th17/Treg imbalance in cells from patients with immune thrombocytopenia. Lab Invest 95:157–167
Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suárez-Fariñas M, Fuentes-Duculan J, Novitskaya I, Khatcherian A, Bluth MJ, Lowes MA, Krueger JG (2007) Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med 204:3183–3194
Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, Ouyang W (2007) Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445:648–651
Acknowledgments
This work received financial support from intramural grants provided by University of Catania, Italy.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Additional information
F. D’Amico and M. C. Mazzarino are the senior authors who contributed equally to this study.
Rights and permissions
About this article
Cite this article
Skarmoutsou, E., Trovato, C., Granata, M. et al. Biological therapy induces expression changes in Notch pathway in psoriasis. Arch Dermatol Res 307, 863–873 (2015). https://doi.org/10.1007/s00403-015-1594-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00403-015-1594-7