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BMC Dermatology
Published in: BMC Dermatology 1/2018

Open Access 01-12-2018 | Research article

Elucidating mechanistic insights into drug action for atopic dermatitis: a systems biology approach

Authors: Indhupriya Subramanian, Vivek K. Singh, Abhay Jere

Published in: BMC Dermatology | Issue 1/2018

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Abstract

Background

Topical Betamethasone (BM) and Pimecrolimus (PC) are widely used drugs in the treatment of atopic dermatitis (AD). Though the biomolecules and biological pathways affected by the drugs are known, the causal inter-relationships among these pathways in the context of skin is not available. We aim to derive this insight by using transcriptomic data of AD skin samples treated with BM and PC using systems biology approach.

Methods

Transcriptomic datasets of 10 AD patients treated with Betamethasone and Pimecrolimus were obtained from GEO datasets. We used a novel computational platform, eSkIN (www.​persistent.​com/​eskin), to perform pathway enrichment analysis for the given datasets. eSkIN consists of 35 skin specific pathways, thus allowing skin-centric analysis of transcriptomic data. Fisher’s exact test was used to compute the significance of the pathway enrichment. The enriched pathways were further analyzed to gain mechanistic insights into the action of these drugs.

Results

Our analysis highlighted the molecular details of the mechanism of action of the drugs and corroborated the known facts about these drugs i.e. BM is more effective in triggering anti-inflammatory response but also causes more adverse effect on skin barrier than PC. In particular, eSkIN helped enunciate the biological pathways activated by these drugs to trigger anti-inflammatory response and its effect on skin barrier. BM suppresses pathways like TNF and TLRs, thus inhibiting NF-κB while PC targets inflammatory genes like IL13 and IL6 via known calcineurin-NFAT pathway. Furthermore, we show that the reduced skin barrier function by BM is due to the suppression of activators like AP1 transcription factors, CEBPs.

Conclusion

We thus demonstrate the detailed mechanistic insight into drug action of AD using a novel computational approach.
Appendix
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Literature
1.
Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66(Suppl 1):8–16.CrossRefPubMed
2.
Jensen JM, et al. Gene expression is differently affected by pimecrolimus and betamethasone in lesional skin of atopic dermatitis. Allergy. 2012;67(3):413–23.CrossRefPubMed
3.
Stojadinovic O, et al. Novel genomic effects of glucocorticoids in epidermal keratinocytes: inhibition of apoptosis, interferon-gamma pathway, and wound healing along with promotion of terminal differentiation. J Biol Chem. 2007;282(6):4021–34.CrossRefPubMed
4.
Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice. Am J Clin Dermatol. 2013;14(3):163–78.CrossRefPubMedPubMedCentral
5.
Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.CrossRef
6.
Huang DW, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37(1):1–13.CrossRef
7.
Subramanian A, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50.CrossRefPubMedPubMedCentral
8.
J.-H. Hung, “Gene set/pathway enrichment analysis,” in Data Mining for Systems Biology, H. Mamitsuka, C. DeLisi, and M. Kanehisa, Eds. Humana Press, 2013, pp. 201–213.
9.
10.
Wu X, et al. Network expansion and pathway enrichment analysis towards biologically significant findings from microarrays. J Integr Bioinforma. 2016;9(2):113–25.
11.
12.
13.
Murphy JE, Robert C, Kupper TS. Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity. J. Invest. Dermatol. 2000;114(3):602–8.CrossRefPubMed
14.
Chen Y, et al. Microarray analysis reveals the inhibition of nuclear factor-kappa B signaling by aristolochic acid in normal human kidney (HK-2) cells. Acta Pharmacol Sin. 2010;31(2):227–36.CrossRefPubMedPubMedCentral
15.
Kaesler S, et al. Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10. J Allergy Clin Immunol. 2014;134(1):92–9.CrossRefPubMed
16.
Hari A, Flach TL, Shi Y, Mydlarski PR. Toll-like receptors: role in dermatological disease. Mediat Inflamm. 2010;2010:437246.CrossRef
17.
Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAK-STAT. 2013;2(3):e24137.CrossRefPubMedPubMedCentral
18.
Im S-H, Rao A. Activation and deactivation of gene expression by Ca2+/calcineurin-NFAT-mediated signaling. Mol Cells. 2004;18(1):1–9.PubMed
19.
Medyouf H, Ghysdael J. The calcineurin/NFAT signaling pathway: a novel therapeutic target in leukemia and solid tumors. Cell Cycle Georget Tex. 2008;7(3):297–303.CrossRef
20.
Murata T, Husain SR, Mohri H, Puri RK. Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway. Int Immunol. 1998;10(8):1103–10.CrossRefPubMed
21.
Wittmann M, Zeitvogel J, Wang D, Werfel T. IL-27 is expressed in chronic human eczematous skin lesions and stimulates human keratinocytes. J Allergy Clin Immunol. 2009;124(1):81–9.CrossRefPubMed
22.
New DC, Wong YH. CC chemokine receptor-coupled signalling pathways. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2003;35(9):779–88.
23.
Pastore S, Mascia F, Mariotti F, Dattilo C, Mariani V, Girolomoni G. ERK1/2 regulates epidermal chemokine expression and skin inflammation. J Immunol Baltim Md 1950. 2005;174(8):5047–56.
24.
Bourguignon LYW, Singleton PA, Diedrich F. Hyaluronan-CD44 interaction with Rac1-dependent protein kinase N-gamma promotes phospholipase Cgamma1 activation, ca(2+) signaling, and cortactin-cytoskeleton function leading to keratinocyte adhesion and differentiation. J Biol Chem. 2004;279(28):29654–69.CrossRefPubMed
25.
Eckert RL, et al. Regulation of involucrin gene expression. J. Invest. Dermatol. 2004;123(1):13–22.CrossRefPubMed
26.
Efimova T, Deucher A, Kuroki T, Ohba M, Eckert RL. Novel protein kinase C isoforms regulate human keratinocyte differentiation by activating a p38 delta mitogen-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha. J Biol Chem. 2002;277(35):31753–60.CrossRefPubMed
27.
Reynolds NJ, et al. Differential induction of phosphatidylcholine hydrolysis, diacylglycerol formation and protein kinase C activation by epidermal growth factor and transforming growth factor-alpha in normal human skin fibroblasts and keratinocytes. Biochem J. 1993;294(Pt 2):535–44.CrossRefPubMedPubMedCentral
28.
Emberley ED, et al. The S100A7-c-Jun activation domain binding protein 1 pathway enhances prosurvival pathways in breast cancer. Cancer Res. 2005;65(13):5696–702.CrossRefPubMed
29.
Uto-Konomi A, et al. Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines. PLoS One. 2012;7(7):e40343.CrossRefPubMedPubMedCentral
30.
Jamora C, Fuchs E. Intercellular adhesion, signalling and the cytoskeleton. Nat Cell Biol. 2002;4(4):E101–8.CrossRefPubMed
31.
Olsson A-K, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 2006;7(5):359–71.CrossRefPubMed
32.
Zambruno G, et al. Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing. J Cell Biol. 1995;129(3):853–65.CrossRefPubMed
33.
Fleischmajer R, et al. Initiation of skin basement membrane formation at the epidermo-dermal interface involves assembly of laminins through binding to cell membrane receptors. J Cell Sci. 1998;111(Pt 14):1929–40.PubMed
34.
Jensen J-M, et al. Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis. J Allergy Clin Immunol. 2009;123(5):1124–33.CrossRefPubMed
35.
Zhang L, Reue K, Fong LG, Young SG, Tontonoz P. Feedback regulation of cholesterol uptake by the LXR-IDOL-LDLR axis. Arterioscler Thromb Vasc Biol. 2012;32(11):2541–6.CrossRefPubMedPubMedCentral
36.
Oda Y, Uchida Y, Moradian S, Crumrine D, Elias PM, Bikle DD. Vitamin D receptor and coactivators SRC2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. J. Invest. Dermatol. 2009;129(6):1367–78.CrossRefPubMed
37.
Yokoyama A, et al. Induction of SREBP-1c mRNA by differentiation and LXR ligand in human keratinocytes. J. Invest. Dermatol. 2009;129(6):1395–401.CrossRefPubMed
38.
Harris IR, et al. Parallel regulation of sterol regulatory element binding protein-2 and the enzymes of cholesterol and fatty acid synthesis but not ceramide synthesis in cultured human keratinocytes and murine epidermis. J Lipid Res. 1998;39(2):412–22.PubMed
39.
Jiang ZG, Robson SC, Yao Z. Lipoprotein metabolism in nonalcoholic fatty liver disease. J Biomed Res. 2013;27(1):1–13.PubMed
40.
Malewicz M, et al. Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair. Genes Dev. 2011;25(19):2031–40.CrossRefPubMedPubMedCentral
41.
Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. 2004;95(11):866–71.CrossRefPubMed
42.
Meng X, Yuan Y, Maestas A, Shen Z. Recovery from DNA damage-induced G2 arrest requires actin-binding protein filamin-a/actin-binding protein 280. J Biol Chem. 2004;279(7):6098–105.CrossRefPubMed
43.
Sulaimon SS, Kitchell BE. The basic biology of malignant melanoma: molecular mechanisms of disease progression and comparative aspects. J Vet Intern Med. 2003;17(6):760–72.CrossRefPubMed
44.
Aktar MK, Kido-Nakahara M, Furue M, Nakahara T. Mutual upregulation of endothelin-1 and IL-25 in atopic dermatitis. Allergy. 2015;70(7):846–54.CrossRefPubMed
45.
Tsybikov NN, Petrisheva IV, Kuznik BI, Magen E. Plasma endothelin-1 levels during exacerbation of atopic dermatitis. Allergy Asthma Proc. 2015;36(4):320–4.CrossRefPubMed
46.
Bouallegue A, Daou GB, Srivastava AK. Endothelin-1-induced signaling pathways in vascular smooth muscle cells. Curr Vasc Pharmacol. 2007;5(1):45–52.CrossRefPubMed
47.
48.
Yamasaki K, et al. Suppressor of cytokine signaling 1/JAB and suppressor of cytokine signaling 3/cytokine-inducible SH2 containing protein 3 negatively regulate the signal transducers and activators of transcription signaling pathway in normal human epidermal keratinocytes. J Invest Dermatol. 2003;120(4):571–80.CrossRefPubMed
Metadata
Title
Elucidating mechanistic insights into drug action for atopic dermatitis: a systems biology approach
Authors
Indhupriya Subramanian
Vivek K. Singh
Abhay Jere
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Dermatology / Issue 1/2018
Electronic ISSN: 1471-5945
DOI
https://doi.org/10.1186/s12895-018-0070-4

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