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• W2088391696 abstract "The innate defense of the skin against microbial threats is influenced by antimicrobial proteins (AMP). Staphylococcus aureus often colonizes the skin of patients with atopic dermatitis (AD). This was explained by diminished expression of AMP including cathelicidin/LL-37, human β-defensins-2 and -3, and dermcidin. The S100-protein psoriasin is an additional keratinocyte-derived AMP that preferentially kills E. coli. As E. coli infections are not observed in atopic skin we investigated the functional role of psoriasin in AD patients. Immunohistochemistry demonstrated enhanced epidermal psoriasin expression in AD. An up to 1500-fold increase in secreted psoriasin was detected by ELISA in vivo on the surface of AD skin compared to healthy control skin. Surprisingly, tumor necrosis factor-α-enhanced psoriasin release in primary keratinocytes was inhibited by the Th2-cytokines IL-4 and -13, whereas IL-17 and -22 induced psoriasin. Epidermal barrier disruption significantly enhanced psoriasin expression as demonstrated by tape stripping in healthy volunteers. The upregulation of psoriasin in AD maybe induced by the disrupted skin barrier offering a possible explanation why these patients do not suffer from skin infections with E. coli. This indicates that the antimicrobial response in AD is not generally impaired, but greatly differs according to the type of AMP produced by the skin. The innate defense of the skin against microbial threats is influenced by antimicrobial proteins (AMP). Staphylococcus aureus often colonizes the skin of patients with atopic dermatitis (AD). This was explained by diminished expression of AMP including cathelicidin/LL-37, human β-defensins-2 and -3, and dermcidin. The S100-protein psoriasin is an additional keratinocyte-derived AMP that preferentially kills E. coli. As E. coli infections are not observed in atopic skin we investigated the functional role of psoriasin in AD patients. Immunohistochemistry demonstrated enhanced epidermal psoriasin expression in AD. An up to 1500-fold increase in secreted psoriasin was detected by ELISA in vivo on the surface of AD skin compared to healthy control skin. Surprisingly, tumor necrosis factor-α-enhanced psoriasin release in primary keratinocytes was inhibited by the Th2-cytokines IL-4 and -13, whereas IL-17 and -22 induced psoriasin. Epidermal barrier disruption significantly enhanced psoriasin expression as demonstrated by tape stripping in healthy volunteers. The upregulation of psoriasin in AD maybe induced by the disrupted skin barrier offering a possible explanation why these patients do not suffer from skin infections with E. coli. This indicates that the antimicrobial response in AD is not generally impaired, but greatly differs according to the type of AMP produced by the skin. atopic dermatitis antimicrobial protein(s) human β-defensins tumor necrosis factor-α In general, the epidermis is constantly exposed to a variety of microbial challenges. The permeability barrier, localized in the stratum corneum, is a mechanical protective hurdle against bacterial infection. The first column in antimicrobial defense is the physical barrier in the stratum corneum, which is supported by the (normal) microflora, antimicrobial lipids, and antimicrobial proteins (AMP; Bibel et al., 1989Bibel D.J. Miller S.J. Brown B.E. Pandey B.B. Elias P.M. Shinefield H.R. et al.Antimicrobial activity of stratum corneum lipids from normal and essential fatty acid-deficient mice.J Invest Dermatol. 1989; 92: 632-638Abstract Full Text PDF PubMed Google Scholar; Elias, 2007Elias P.M. The skin barrier as an innate immune element.Semin Immunopathol. 2007; 29: 3-14Crossref PubMed Scopus (265) Google Scholar; Jensen et al., 2007Jensen J.M. Pfeiffer S. Akaki T. Schröder J.M. Kleine M. Neumann C. et al.Barrier function, epidermal differentiation, and human beta-defensin 2 expression in tinea corporis.J Invest Dermatol. 2007; 127: 1720-1727Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar; Aberg et al., 2008Aberg K.M. Man M.Q. Gallo R.L. Ganz T. Crumrine D. Brown B.E. et al.Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers.J Invest Dermatol. 2008; 128: 917-925Crossref PubMed Scopus (181) Google Scholar). Impairment of the physical barrier by injury is a prerequisite for experimental skin infection by the application of a bacterial suspension (Singh et al., 1971Singh G. Marples R.R. Kligman A.M. Experimental Staphylococcus aureus infections in humans.J Invest Dermatol. 1971; 57: 149-162Crossref PubMed Scopus (52) Google Scholar). In atopic dermatitis (AD) and psoriasis vulgaris, skin diseases that are associated with a disturbed permeability barrier function, the epidermis is colonized with a higher rate and potentially pathogenic microorganisms (Aly et al., 1976Aly R. Maibach H.E. Mandel A. Bacterial flora in psoriasis.Br J Dermatol. 1976; 95: 603-606Crossref PubMed Scopus (53) Google Scholar, Aly et al., 1977Aly R. Maibach H.I. Shinefield H.R. Microbial flora of atopic dermatitis.Arch Dermatol. 1977; 113: 780-782Crossref PubMed Scopus (221) Google Scholar; Leung, 2003Leung D.Y. Infection in atopic dermatitis.Curr Opin Pediatr. 2003; 15: 399-404Crossref PubMed Scopus (133) Google Scholar; Baker, 2006Baker B.S. The role of microorganisms in atopic dermatitis.Clin Exp Immunol. 2006; 144: 1-9Crossref PubMed Scopus (211) Google Scholar). In a mouse model with a chronically impaired skin barrier induced by an essential fatty acid-deficient diet, microbial colonization with Staphylococcus aureus was enhanced (Bibel et al., 1989Bibel D.J. Miller S.J. Brown B.E. Pandey B.B. Elias P.M. Shinefield H.R. et al.Antimicrobial activity of stratum corneum lipids from normal and essential fatty acid-deficient mice.J Invest Dermatol. 1989; 92: 632-638Abstract Full Text PDF PubMed Google Scholar). Despite significant changes in bacterial colonization and an impaired permeability barrier, psoriatic epidermis is usually free of the symptoms of infection (Henseler and Christophers, 1995Henseler T. Christophers E. Disease concomitance in psoriasis.J Am Acad Dermatol. 1995; 32: 982-986Abstract Full Text PDF PubMed Scopus (573) Google Scholar), whereas in AD, clinical signs of impetiginization are predominantly found in severe cases and after extensive scratching (Lubbe, 2003Lubbe J. Secondary infections in patients with atopic dermatitis.Am J Clin Dermatol. 2003; 4: 641-654Crossref PubMed Scopus (87) Google Scholar). Nevertheless, both diseases can be aggravated by bacterial “superantigens” that bypass the normal control of T-cell activation (Skov and Baadsgaard, 2000Skov L. Baadsgaard O. Bacterial superantigens and inflammatory skin diseases.Clin Exp Dermatol. 2000; 25: 57-61Crossref PubMed Scopus (83) Google Scholar) and colonization with superantigen- and toxin-producing S. aureus can aggravate the disease. The unexpected low incidence of infections in psoriatic skin suggests additional cutaneous defense mechanisms besides the physical barrier. One of these defense mechanisms comprises the production of AMP, which are found abundant in lesional psoriatic scales (Harder and Schröder, 2005aHarder J. Schröder J.M. Antimicrobial peptides in human skin.Chem Immunol Allergy. 2005; 86: 22-41Crossref PubMed Scopus (93) Google Scholar, Harder and Schröder, 2005bHarder J. Schröder J.M. Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins.J Leukoc Biol. 2005; 77: 476-486Crossref PubMed Scopus (184) Google Scholar) and are generated by various epithelial cells (reviewed in (Ganz and Lehrer, 1998Ganz T. Lehrer R.I. Antimicrobial peptides of vertebrates.Curr Opin Immunol. 1998; 10: 41-44Crossref PubMed Scopus (330) Google Scholar; Schröder and Harder, 2006Schröder J.M. Harder J. Antimicrobial skin peptides and proteins.Cell Mol Life Sci. 2006; 63: 469-486Crossref PubMed Scopus (203) Google Scholar)). Several types of AMP including the human β-defensins (hBD) 1–3 (Fulton et al., 1997Fulton C. Anderson G.M. Zasloff M. Bull R. Quinn A.G. Expression of natural peptide antibiotics in human skin.Lancet. 1997; 350: 1750-1751Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar; Harder et al., 1997Harder J. Bartels J. Christophers E. Schröder J.M. A peptide antibiotic from human skin.Nature. 1997; 387: 861Crossref PubMed Scopus (1162) Google Scholar, Harder et al., 2001Harder J. Bartels J. Christophers E. Schröder J.M. Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic.J Biol Chem. 2001; 276: 5707-5713Crossref PubMed Scopus (1125) Google Scholar, Harder et al., 2004Harder J. Meyer-Hoffert U. Wehkamp K. Schwichtenberg L. Schröder J.M. Differential gene induction of human beta-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid.J Invest Dermatol. 2004; 123: 522-529Crossref PubMed Scopus (183) Google Scholar), the cathelicidin LL-37 (Frohm et al., 1997Frohm M. Agerberth B. Ahangari G. Stahle-Backdahl M. Liden S. Wigzell H. et al.The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders.J Biol Chem. 1997; 272: 15258-15263Crossref PubMed Scopus (649) Google Scholar), dermcidin (Schittek et al., 2001Schittek B. Hipfel R. Sauer B. Bauer J. Kalbacher H. Stevanovic S. et al.Dermcidin: a novel human antibiotic peptide secreted by sweat glands.Nat Immunol. 2001; 2: 1133-1137Crossref PubMed Scopus (475) Google Scholar), RNase-7 (Harder and Schröder, 2002Harder J. Schröder J.M. RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin.J Biol Chem. 2002; 277: 46779-46784Crossref PubMed Scopus (325) Google Scholar), and psoriasin (Gläser et al., 2005Gläser R. Harder J. Lange H. Bartels J. Christophers E. Schröder J.M. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection.Nat Immunol. 2005; 6: 57-64Crossref PubMed Scopus (489) Google Scholar) were identified in human skin. Keratinocyte-derived AMPs protect healthy skin from surrounding microorganisms and may regulate the composition of the normal flora (Dinulos et al., 2003Dinulos J.G. Mentele L. Fredericks L.P. Dale B.A. Darmstadt G.L. Keratinocyte expression of human beta defensin 2 following bacterial infection: role in cutaneous host defense.Clin Diagn Lab Immunol. 2003; 10: 161-166Crossref PubMed Scopus (77) Google Scholar; Chung and Dale, 2004Chung W.O. Dale B.A. Innate immune response of oral and foreskin keratinocytes: utilization of different signaling pathways by various bacterial species.Infect Immun. 2004; 72: 352-358Crossref PubMed Scopus (153) Google Scholar). Some of the AMPs (hBD-1, RNase-7, lysozyme) are constitutively expressed by keratinocytes (Harder et al., 2007Harder J. Gläser R. Schröder J.M. Review: human antimicrobial proteins effectors of innate immunity.J Endotoxin Res. 2007; 13: 317-338Crossref PubMed Scopus (80) Google Scholar). A few—such as psoriasin—are focally present at different levels in healthy skin (Gläser et al., 2005Gläser R. Harder J. Lange H. Bartels J. Christophers E. Schröder J.M. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection.Nat Immunol. 2005; 6: 57-64Crossref PubMed Scopus (489) Google Scholar) and inducible upon skin inflammation (Madsen et al., 1991Madsen P. Rasmussen H.H. Leffers H. Honore B. Dejgaard K. Olsen E. et al.Molecular cloning, occurrence, and expression of a novel partially secreted protein “psoriasin” that is highly up-regulated in psoriatic skin.J Invest Dermatol. 1991; 97: 701-712Abstract Full Text PDF PubMed Google Scholar) or wounding (Lee and Eckert, 2007Lee K.C. Eckert R.L. S100A7 (Psoriasin)—mechanism of antibacterial action in wounds.J Invest Dermatol. 2007; 127: 945-957Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar), whereas others (hBD-2, -3, LL-37) are found only in inflamed but not in healthy skin (Abiko et al., 2002Abiko Y. Jinbu Y. Noguchi T. Nishimura M. Kusano K. Amaratunga P. et al.Upregulation of human beta-defensin 2 peptide expression in oral lichen planus, leukoplakia and candidiasis. An immunohistochemical study.Pathol Res Pract. 2002; 198: 537-542Crossref PubMed Scopus (41) Google Scholar; Sorensen et al., 2003Sorensen O.E. Cowland J.B. Theilgaard-Monch K. Liu L. Ganz T. Borregaard N. Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors.J Immunol. 2003; 170: 5583-5589Crossref PubMed Scopus (294) Google Scholar, Sorensen et al., 2005Sorensen O.E. Thapa D.R. Rosenthal A. Liu L. Roberts A.A. Ganz T. Differential regulation of {beta}-defensin expression in human skin by microbial stimuli.J Immunol. 2005; 174: 4870-4879Crossref PubMed Scopus (198) Google Scholar; Li et al., 2004Li D. Li J. Duan Y. Zhou X. Expression of LL-37, human beta defensin-2, and CCR6 mRNA in patients with psoriasis vulgaris.J Huazhong Univ Sci Technolog Med Sci. 2004; 24: 404-406Crossref PubMed Google Scholar; Harder and Schröder, 2005aHarder J. Schröder J.M. Antimicrobial peptides in human skin.Chem Immunol Allergy. 2005; 86: 22-41Crossref PubMed Scopus (93) Google Scholar, Harder and Schröder, 2005bHarder J. Schröder J.M. Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins.J Leukoc Biol. 2005; 77: 476-486Crossref PubMed Scopus (184) Google Scholar). AMP are inducible by proinflammatory cytokines including IL-1β, tumor necrosis factor-α (TNF-α) (Harder et al., 2000Harder J. Meyer-Hoffert U. Teran L.M. Schwichtenberg L. Bartels J. Maune S. et al.Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia.Am J Respir Cell Mol Biol. 2000; 22: 714-721Crossref PubMed Scopus (371) Google Scholar, Harder et al., 2004Harder J. Meyer-Hoffert U. Wehkamp K. Schwichtenberg L. Schröder J.M. Differential gene induction of human beta-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid.J Invest Dermatol. 2004; 123: 522-529Crossref PubMed Scopus (183) Google Scholar), IL-17 and -22 (Liang et al., 2006Liang S.C. Tan X.Y. Luxenberg D.P. Karim R. Dunussi-Joannopoulos K. Collins M. et al.Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides.J Exp Med. 2006; 203: 2271-2279Crossref PubMed Scopus (1688) Google Scholar; Wolk et al., 2006Wolk K. Witte E. Wallace E. Docke W.D. Kunz S. Asadullah K. et al.IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis.Eur J Immunol. 2006; 36: 1309-1323Crossref PubMed Scopus (716) Google Scholar), after bacterial contact (Harder et al., 2000Harder J. Meyer-Hoffert U. Teran L.M. Schwichtenberg L. Bartels J. Maune S. et al.Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia.Am J Respir Cell Mol Biol. 2000; 22: 714-721Crossref PubMed Scopus (371) Google Scholar; Kisich et al., 2007Kisich K.O. Howell M.D. Boguniewicz M. Heizer H.R. Watson N.U. Leung D.Y. The constitutive capacity of human keratinocytes to kill Staphylococcus aureus is dependent on beta-defensin 3.J Invest Dermatol. 2007; 127: 2368-2380Crossref PubMed Scopus (111) Google Scholar), during epidermal differentiation (Harder et al., 2004Harder J. Meyer-Hoffert U. Wehkamp K. Schwichtenberg L. Schröder J.M. Differential gene induction of human beta-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid.J Invest Dermatol. 2004; 123: 522-529Crossref PubMed Scopus (183) Google Scholar) or wound healing (Sorensen et al., 2003Sorensen O.E. Cowland J.B. Theilgaard-Monch K. Liu L. Ganz T. Borregaard N. Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors.J Immunol. 2003; 170: 5583-5589Crossref PubMed Scopus (294) Google Scholar). In addition, the expression of LL-37 in keratinocytes appears to be induced by 1,25(OH)2 vitamin D3 (Wang et al., 2004Wang T.T. Nestel F.P. Bourdeau V. Nagai Y. Wang Q. Liao J. et al.Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.J Immunol. 2004; 173: 2909-2912Crossref PubMed Scopus (1122) Google Scholar; Weber et al., 2005Weber G. Heilborn J.D. Chamorro Jimenez C.I. Hammarsjo A. Torma H. Stahle M. Vitamin D induces the antimicrobial protein hCAP18 in human skin.J Invest Dermatol. 2005; 124: 1080-1082Crossref PubMed Scopus (186) Google Scholar; Schauber et al., 2007Schauber J. Dorschner R.A. Coda A.B. Buchau A.S. Liu P.T. Kiken D. et al.Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism.J Clin Invest. 2007; 117: 803-811Crossref PubMed Scopus (529) Google Scholar). Recently, we identified the S100-protein psoriasin as an additional AMP in healthy human epidermis (Gläser et al., 2005Gläser R. Harder J. Lange H. Bartels J. Christophers E. Schröder J.M. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection.Nat Immunol. 2005; 6: 57-64Crossref PubMed Scopus (489) Google Scholar). At lower doses, psoriasin preferentially kills E. coli. At higher concentrations, however, it exhibits also bactericidal activity against Pseudomonas aeruginosa and S. aureus. Psoriasin, originally identified from psoriatic keratinocytes (Madsen et al., 1991Madsen P. Rasmussen H.H. Leffers H. Honore B. Dejgaard K. Olsen E. et al.Molecular cloning, occurrence, and expression of a novel partially secreted protein “psoriasin” that is highly up-regulated in psoriatic skin.J Invest Dermatol. 1991; 97: 701-712Abstract Full Text PDF PubMed Google Scholar), is constitutively expressed at rather high levels in skin and upregulated by proinflammatory cytokines or bacterial compounds (Gläser et al., 2005Gläser R. Harder J. Lange H. Bartels J. Christophers E. Schröder J.M. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection.Nat Immunol. 2005; 6: 57-64Crossref PubMed Scopus (489) Google Scholar). Psoriasin was also shown to function as a potent T-cell- and neutrophil-chemotactic agent (Jinquan et al., 1996Jinquan T. Vorum H. Larsen C.G. Madsen P. Rasmussen H.H. Gesser B. et al.Psoriasin: a novel chemotactic protein.J Invest Dermatol. 1996; 107: 5-10Crossref PubMed Scopus (210) Google Scholar; Zheng et al., 2008Zheng Y. Niyonsaba F. Ushio H. Ikeda S. Nagaoka I. Okumura K. et al.Microbicidal protein psoriasin is a multifunctional modulator of neutrophil activation.Immunology. 2008; 124: 357-367Crossref PubMed Scopus (75) Google Scholar). Patients with AD often suffer from skin infections caused by bacteria and viruses (Leung, 2003Leung D.Y. Infection in atopic dermatitis.Curr Opin Pediatr. 2003; 15: 399-404Crossref PubMed Scopus (133) Google Scholar; Wollenberg et al., 2003Wollenberg A. Wetzel S. Burgdorf W.H. Haas J. Viral infections in atopic dermatitis: pathogenic aspects and clinical management.J Allergy Clin Immunol. 2003; 112: 667-674Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). Among bacterial superinfections S. aureus is the predominant pathogen. Approximately 90% of AD patients were shown to be colonized with S. aureus compared to only 5–30% in a control population (Leung, 2003Leung D.Y. Infection in atopic dermatitis.Curr Opin Pediatr. 2003; 15: 399-404Crossref PubMed Scopus (133) Google Scholar). Previously unknown observations suggest that an impaired expression of AMP may contribute to the increased susceptibility of AD skin to S. aureus. It has been demonstrated that the AMP hBD-2 and LL-37 are expressed to a lesser extent in the epidermis of AD patients, when compared to psoriatic epidermis (Ong et al., 2002Ong P.Y. Ohtake T. Brandt C. Strickland I. Boguniewicz M. Ganz T. et al.Endogenous antimicrobial peptides and skin infections in atopic dermatitis.N Engl J Med. 2002; 347: 1151-1160Crossref PubMed Scopus (1549) Google Scholar). Another study reported a disturbed upregulation of hBD-3 in AD skin (Nomura et al., 2003aNomura I. Gao B. Boguniewicz M. Darst M.A. Travers J.B. Leung D.Y. Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis.J Allergy Clin Immunol. 2003; 112: 1195-1202Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, Nomura et al., 2003bNomura I. Goleva E. Howell M.D. Hamid Q.A. Ong P.Y. Hall C.F. et al.Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.J Immunol. 2003; 171: 3262-3269Crossref PubMed Scopus (617) Google Scholar). This may be of particular importance because hBD-3 is known to be an important AMP produced by keratinocytes to control the growth of S. aureus (Kisich et al., 2007Kisich K.O. Howell M.D. Boguniewicz M. Heizer H.R. Watson N.U. Leung D.Y. The constitutive capacity of human keratinocytes to kill Staphylococcus aureus is dependent on beta-defensin 3.J Invest Dermatol. 2007; 127: 2368-2380Crossref PubMed Scopus (111) Google Scholar). In addition, the sweat gland-derived AMP dermcidin was found to be diminished in AD patients (Rieg et al., 2005Rieg S. Steffen H. Seeber S. Humeny A. Kalbacher H. Dietz K. et al.Deficiency of dermcidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis correlates with an impaired innate defense of human skin in vivo.J Immunol. 2005; 174: 8003-8010Crossref PubMed Scopus (217) Google Scholar). Together, these data support the hypothesis that a deficiency of AMP could contribute to the increased susceptibility of AD skin to infection with S. aureus. Interestingly, AD patients do not suffer from skin infections caused by E. coli, although this is the most common gut bacterium (Baker, 2006Baker B.S. The role of microorganisms in atopic dermatitis.Clin Exp Immunol. 2006; 144: 1-9Crossref PubMed Scopus (211) Google Scholar). On the basis of the recently discovered potent E. coli-cidal activity (Gläser et al., 2005Gläser R. Harder J. Lange H. Bartels J. Christophers E. Schröder J.M. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection.Nat Immunol. 2005; 6: 57-64Crossref PubMed Scopus (489) Google Scholar; Li et al., 2005Li X. de Leeuw E. Lu W. Total chemical synthesis of human psoriasin by native chemical ligation.Biochemistry. 2005; 44: 14688-14694Crossref PubMed Scopus (21) Google Scholar), we hypothesized that psoriasin expression might be increased in AD patients, thereby contributing to the resistance of atopic epidermis to E. coli infections despite the impaired epidermal barrier. Here, we show that psoriasin indeed is enhanced in AD and thus differently regulated than the other AMP. We also provide evidence that the increased expression of psoriasin may be driven by the disrupted epidermal barrier, representing a kind of autoprotective mechanism. The expression of psoriasin in the epidermis was first examined at the protein level by immunostaining using a specific antibody. For that purpose, biopsies were taken from four AD patients. Lesional skin of all four patients revealed increased psoriasin expression compared to nonlesional skin and control biopsies of healthy volunteers at the same anatomical localization (Figure 1a). The intensity of psoriasin immunostaining in the lesional skin of AD patients was comparable to that found in lesional psoriatic skin (Figure 1b). To investigate whether the increased psoriasin expression in the skin of patients with AD leads to enhanced secretion of psoriasin, washing fluids of standardized areas of nonlesional and lesional skin were obtained and analyzed for psoriasin concentrations using a specific psoriasin ELISA. A markedly enhanced secretion with up to 1500-fold increase of soluble psoriasin was observed in the washing fluids derived from AD lesional skin when compared to nonlesional skin and normal controls (Figure 2). Notably nonlesional skin exhibited significantly enhanced levels of secreted psoriasin when compared to healthy control skin. The difference between nonlesional and lesional atopic skin was also shown to be significant (P<0.0005). The Th2 cytokines IL-4 and -13 were found to be increased in AD skin and have been attributed to be responsible for the downregulation of hBD-2 and -3 and the cathelicidin LL-37 (Ong et al., 2002Ong P.Y. Ohtake T. Brandt C. Strickland I. Boguniewicz M. Ganz T. et al.Endogenous antimicrobial peptides and skin infections in atopic dermatitis.N Engl J Med. 2002; 347: 1151-1160Crossref PubMed Scopus (1549) Google Scholar; Nomura et al., 2003aNomura I. Gao B. Boguniewicz M. Darst M.A. Travers J.B. Leung D.Y. Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis.J Allergy Clin Immunol. 2003; 112: 1195-1202Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, Nomura et al., 2003bNomura I. Goleva E. Howell M.D. Hamid Q.A. Ong P.Y. Hall C.F. et al.Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.J Immunol. 2003; 171: 3262-3269Crossref PubMed Scopus (617) Google Scholar). Thus, we asked in turn whether both cytokines are involved in the regulation of psoriasin as well. To address this issue, cultured primary keratinocytes were stimulated with the Th2 cytokines IL-4 and -13 alone and in combination with the proinflammatory cytokine TNF-α that was shown to be upregulated in the epidermis of patients with AD (Sumimoto et al., 1992Sumimoto S. Kawai M. Kasajima Y. Hamamoto T. Increased plasma tumour necrosis factor-alpha concentration in atopic dermatitis.Arch Dis Child. 1992; 67: 277-279Crossref PubMed Scopus (64) Google Scholar; Ackermann and Harvima, 1998Ackermann L. Harvima I.T. Mast cells of psoriatic and atopic dermatitis skin are positive for TNF-alpha and their degranulation is associated with expression of ICAM-1 in the epidermis.Arch Dermatol Res. 1998; 290: 353-359Crossref PubMed Scopus (132) Google Scholar; de Vries et al., 1998de Vries I.J. Langeveld-Wildschut E.G. van Reijsen F.C. Dubois G.R. van den Hoek J.A. Bihari I.C. et al.Adhesion molecule expression on skin endothelia in atopic dermatitis: effects of TNF-alpha and IL-4.J Allergy Clin Immunol. 1998; 102: 461-468Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar; Junghans et al., 1998Junghans V. Gutgesell C. Jung T. Neumann C. Epidermal cytokines IL-1beta, TNF-alpha, and IL-12 in patients with atopic dermatitis: response to application of house dust mite antigens.J Invest Dermatol. 1998; 111: 1184-1188Crossref PubMed Scopus (60) Google Scholar; Antunez et al., 2006Antunez C. Torres M.J. Mayorga C. Corzo J.L. Jurado A. Santamaria-Babi L.F. et al.Cytokine production, activation marker, and skin homing receptor in children with atopic dermatitis and bronchial asthma.Pediatr Allergy Immunol. 2006; 17: 166-174Crossref PubMed Scopus (27) Google Scholar). Secreted psoriasin was determined in the supernatants by ELISA (Figure 3a). Stimulation with TNF-α significantly induced the release of psoriasin, whereas neither IL-4 nor IL-13 had a significant impact on the basal psoriasin expression. In contrast, both IL-4 and -13 markedly inhibited the induction of psoriasin by TNF-α. The combination of IL-4 and -13 did not yield an additive or synergistic inhibitory effect. As recently a possible pathogenic role of Th17 cells was reported for AD (Koga et al., 2008Koga C. Kabashima K. Shiraishi N. Kobayashi M. Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis.J Invest Dermatol. 2008Crossref Scopus (468) Google Scholar), primary keratinocytes were additionally stimulated with IL-17 and/or -22. An enhanced secretion of psoriasin was observed 16hour after stimulation with both cytokines and the combination of IL-17 and -22 resulted in an additive effect (Figure 3b). Stimulation of keratinocytes with IL-17 and -22 in the presence of Th2 cytokines IL-4 and -13 did not alter upregulated psoriasin secretion (data not shown). As it is known that patients with AD exhibit skin barrier disruption with enhanced levels of transepidermal water loss (Loden et al., 1992Loden M. Olsson H. Axell T. Linde Y.W. Friction, capacitance and transepidermal water loss (TEWL) in dry atopic and normal skin.Br J Dermatol. 1992; 126: 137-141Crossref PubMed Scopus (183) Google Scholar; Jensen et al., 2004Jensen J.M. Folster-Holst R. Baranowsky A. Schunck M. Winoto-Morbach S. Neumann C. et al.Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis.J Invest Dermatol. 2004; 122: 1423-1431Crossref PubMed Scopus (244) Google Scholar), we hypothesized that an artificial disruption of the epidermal barrier could lead to an increase in psoriasin secretion. Indeed, a rapid increase of soluble psoriasin was observed directly after tape stripping. Increased soluble psoriasin was measured at nearly constant levels 30 and 120minutes after skin injury performed in healthy volunteers (n=12, Figure 4a). Most interestingly, secretion of psoriasin remained elevated even 7 days after skin barrier disruption. To investigate the influence of experimental barrier repair on psoriasin expression, additional experiments were performed under occlusion (n=8). Washing fluids collected at two time points showed enhanced expression 1 and 24hour after tape stripping, independently from occlusion (Figure 4b). Median psoriasin concentrations rose from 2.63ng/ml (0.86–7.61) after 1hour to 10.95ng/ml (5.26–67.90) without occlusion (P<0.01) and 5.88ng/ml (1.87–36.85) under occlusion. At 24hour after tape stripping median psoriasin concentrations were at 7.52ng/ml (1.54–27.13) without (P<0.01) and" @default.
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• W2088391696 date "2009-03-01" @default.
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• W2088391696 title "The Antimicrobial Protein Psoriasin (S100A7) Is Upregulated in Atopic Dermatitis and after Experimental Skin Barrier Disruption" @default.
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• W2088391696 doi "https://doi.org/10.1038/jid.2008.268" @default.
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