Background: Discovery of the significant impact of filaggrin (FLG) mutations on the genetic predisposition to atopic dermatitis (AD) focused attention on the 1q21 locus, where not only FLG but also other epidermal genes are located. In the present study, we compared 1q21 gene expression in lesional versus nonlesional AD skin. Methods: A real-time quantitative PCR analysis of 10 1q21 genes, selected on the basis of a previous microarray study, was performed in skin biopsies from 33 individuals with AD. Three alternative pathway keratins were also evaluated. Results: In chronic AD skin lesions, we observed an increase in RNA encoding involucrin, S100 calcium-binding proteins A2 and A7–A9 and small proline-rich region (SPRR) proteins 1A and 2C, with fold changes ranging from 2.0 for S100A2 to 15.4 for S100A8 (p < 0.001, Bonferroni corrected), in parallel to the overexpression of the alternative pathway keratins 6A, 6B and 16. The loricrin (LOR) expression level was significantly decreased in lesional AD skin (fold change 0.5; p < 0.01). The expression of the majority of 1q21 genes and alternative keratins was closely correlated; however, for SPRR1A (and SPRR2C) in lesional skin, the correlation with other genes was lost. Conclusions: We hypothesize that the deregulated increase in SPRR1A expression in chronic atopic skin lesions reflects an insufficient rise in SPRR transcripts, unable to compensate for the lack of LOR and thus contributing to the persistence of chronic AD skin lesions. Turning off the stress response in the skin may be regarded as a goal in the treatment of AD skin lesions, and SPRR genes might be targets for such an approach.

Keywords:
Epidermal differentiation complex, Atopic dermatitis, Cornified envelope, Gene expression, Real-time quantitative PCR
1.
Eckert RL, Sturniolo MT, Broome AM, Ruse M, Rorke EA: Transglutaminase function in epidermis. J Invest Dermatol 2005;124:481–492.
2.
Presland RB, Dale BA: Epithelial structural proteins of the skin and oral cavity: function in health and disease. Crit Rev Oral Biol Med 2000;11:383–408.
3.
Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH: Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38:441–446.
4.
Sandilands A, Terron-Kwiatkowski A, Hull PR, O’Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M, Gruber R, Janecke AR, Elias PM, van Steensel MA, Nagtzaam I, van Geel M, Steijlen PM, Munro CS, Bradley DG, Palmer CN, Smith FJ, McLean WH, Irvine AD: Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 2007;39:650–654.
5.
Seguchi T, Cui CY, Kusuda S, Takahashi M, Aisu K, Tezuka T: Decreased expression of filaggrin in atopic skin. Arch Dermatol Res 1996;288:442–446.
6.
Sugiura H, Ebise H, Tazawa T, Tanaka K, Sugiura Y, Uehara M, Kikuchi K, Kimura T: Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope. Br J Dermatol 2005;152:146–149.
7.
Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY: Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007;120:150–155.
8.
Mischke D, Korge BP, Marenholz I, Volz A, Ziegler A: Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (‘epidermal differentiation complex’) on human chromosome 1q21. J Invest Dermatol 1996;106:989–992.
9.
Eckert RL, Broome AM, Ruse M, Robinson N, Ryan D, Lee K: S100 proteins in the epidermis. J Invest Dermatol 2004;123:23–33.
10.
Takaishi M, Makino T, Morohashi M, Huh NH: Identification of human hornerin and its expression in regenerating and psoriatic skin. J Biol Chem 2005;280:4696–4703.
11.
Marshall D, Hardman MJ, Nield KM, Byrne C: Differentially expressed late constituents of the epidermal cornified envelope. Proc Natl Acad Sci USA 2001;98:13031–13036.
12.
Hitomi K: Transglutaminases in skin epidermis. Eur J Dermatol 2005;15:313–319.
13.
Hirao T, Terui T, Takeuchi I, Kobayashi H, Okada M, Takahashi M, Tagami H: Ratio of immature cornified envelopes does not correlate with parakeratosis in inflammatory skin disorders. Exp Dermatol 2003;12:591–601.
14.
Jensen JM, Folster-Holst R, Baranowsky A, Schunck M, Winoto-Morbach S, Neumann C, Schutze S, Proksch E: Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. J Invest Dermatol 2004;122:1423–1431.
15.
Jang SI, Steinert PM: Loricrin expression in cultured human keratinocytes is controlled by a complex interplay between transcription factors of the Sp1, CREB, AP1, and AP2 families. J Biol Chem 2002;277:42268–42279.
16.
Segre JA: Epidermal barrier formation and recovery in skin disorders. J Clin Invest 2006;116:1150–1158.
17.
Kunz B, Oranje AP, Labreze L, Stalder JF, Ring J, Taieb A: Clinical validation and guidelines for the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis. Dermatology 1997;195:10–19.
18.
Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001;29:e45.
19.
Cikos S, Bukovska A, Koppel J: Relative quantification of mRNA: comparison of methods currently used for real-time PCR data analysis. BMC Mol Biol 2007;8:113.
20.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002;3:research0034.1–0034.11.
21.
Koch PJ, de Viragh PA, Scharer E, Bundman D, Longley MA, Bickenbach J, Kawachi Y, Suga Y, Zhou Z, Huber M, Hohl D, Kartasova T, Jarnik M, Steven AC, Roop DR: Lessons from loricrin-deficient mice: compensatory mechanisms maintaining skin barrier function in the absence of a major cornified envelope protein. J Cell Biol 2000;151:389–400.
22.
De Heller-Milev M, Huber M, Panizzon R, Hohl D: Expression of small proline rich proteins in neoplastic and inflammatory skin diseases. Br J Dermatol 2000;143:733–740.
23.
Cabral A, Voskamp P, Cleton-Jansen AM, South A, Nizetic D, Backendorf C: Structural organization and regulation of the small proline-rich family of cornified envelope precursors suggest a role in adaptive barrier function. J Biol Chem 2001;276:19231–19237.
24.
Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, Darst MA, Gao B, Boguniewicz M, Travers JB, Leung DY: Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol 2003;171:3262–3269.
25.
Crish JF, Gopalakrishnan R, Bone F, Gilliam AC, Eckert RL: The distal and proximal regulatory regions of the involucrin gene promoter have distinct functions and are required for in vivo involucrin expression. J Invest Dermatol 2006;126:305–314.
26.
Hohl D: Expression patterns of loricrin in dermatological disorders. Am J Dermatopathol 1993;15:20–27.
27.
Xu X, Kawachi Y, Nakamura Y, Sakurai H, Hirota A, Banno T, Takahashi T, Roop DR, Otsuka F: Yin-yang 1 negatively regulates the differentiation-specific transcription of mouse loricrin gene in undifferentiated keratinocytes. J Invest Dermatol 2004;123:1120–1126.
28.
Mehrel T, Hohl D, Rothnagel JA, Longley MA, Bundman D, Cheng C, Lichti U, Bisher ME, Steven AC, Steinert PM, et al: Identification of a major keratinocyte cell envelope protein, loricrin. Cell 1990;61:1103–1112.
29.
Broome AM, Ryan D, Eckert RL: S100 protein subcellular localization during epidermal differentiation and psoriasis. J Histochem Cytochem 2003;51:675–685.
30.
Eue I, Konig S, Pior J, Sorg C: S100A8, S100A9 and the S100A8/A9 heterodimer complex specifically bind to human endothelial cells: identification and characterization of ligands for the myeloid-related proteins S100A9 and S100A8/A9 on human dermal microvascular endothelial cell line-1 cells. Int Immunol 2002;14:287–297.
31.
Yui S, Nakatani Y, Mikami M: Calprotectin (S100A8/S100A9), an inflammatory protein complex from neutrophils with a broad apoptosis-inducing activity. Biol Pharm Bull 2003;26:753–760.
32.
Marenholz I, Nickel R, Ruschendorf F, Schulz F, Esparza-Gordillo J, Kerscher T, Gruber C, Lau S, Worm M, Keil T, Kurek M, Zaluga E, Wahn U, Lee YA: Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol 2006;118:866–871.
33.
Olsen E, Rasmussen HH, Celis JE: Identification of proteins that are abnormally regulated in differentiated cultured human keratinocytes. Electrophoresis 1995;16:2241– 2248.
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2009
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