Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency
Background Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patient...
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| creator | Kezic, Sanja, PhD O’Regan, Gráinne M., MRCPI Lutter, René, PhD Jakasa, Ivone, PhD Koster, Ellen S., PhD Saunders, Sean, BSc Caspers, Peter, PhD Kemperman, Patrick M.J.H., MD Puppels, Gerwin J., PhD Sandilands, Aileen, PhD Chen, Huijia, PhD Campbell, Linda E., BSc Kroboth, Karin, MSc Watson, Rosemarie, MD Fallon, Padraic G., PhD McLean, W. H. Irwin, DSc, FMedSci Irvine, Alan D., MD, FRCPI |
| description | Background Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD FLG ) compared with that seen in patients with AD without these mutations (AD NON-FLG ). Objectives We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD FLG versus patients with AD NON-FLG . We also sought to examine the same profiles in a murine model of filaggrin deficiency ( Flgft /Flgft [ FlgdelAPfal ] mice). Methods One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1α, IL-1β, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flgft /Flgft (FlgdelAPfal ) mice, separated from maFlgft /maFlgft (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1α, IL-1β, and IL-1RA. Results SC IL-1 levels were increased in patients with AD FLG ; these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flgft /Flgft mice had upregulated expression of IL-1β and IL-1RA mRNA. Conclusions AD FLG is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches. |
| doi_str_mv | 10.1016/j.jaci.2011.12.989 |
| format | Article |
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H. Irwin, DSc, FMedSci ; Irvine, Alan D., MD, FRCPI</creator><creatorcontrib>Kezic, Sanja, PhD ; O’Regan, Gráinne M., MRCPI ; Lutter, René, PhD ; Jakasa, Ivone, PhD ; Koster, Ellen S., PhD ; Saunders, Sean, BSc ; Caspers, Peter, PhD ; Kemperman, Patrick M.J.H., MD ; Puppels, Gerwin J., PhD ; Sandilands, Aileen, PhD ; Chen, Huijia, PhD ; Campbell, Linda E., BSc ; Kroboth, Karin, MSc ; Watson, Rosemarie, MD ; Fallon, Padraic G., PhD ; McLean, W. H. Irwin, DSc, FMedSci ; Irvine, Alan D., MD, FRCPI</creatorcontrib><description>Background Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD FLG ) compared with that seen in patients with AD without these mutations (AD NON-FLG ). Objectives We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD FLG versus patients with AD NON-FLG . We also sought to examine the same profiles in a murine model of filaggrin deficiency ( Flgft /Flgft [ FlgdelAPfal ] mice). Methods One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1α, IL-1β, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flgft /Flgft (FlgdelAPfal ) mice, separated from maFlgft /maFlgft (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1α, IL-1β, and IL-1RA. Results SC IL-1 levels were increased in patients with AD FLG ; these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flgft /Flgft mice had upregulated expression of IL-1β and IL-1RA mRNA. Conclusions AD FLG is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches.</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2011.12.989</identifier><identifier>PMID: 22322004</identifier><identifier>CODEN: JACIBY</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Adolescent ; Alleles ; Allergic diseases ; Allergy and Immunology ; Animal models ; Animals ; Atopic dermatitis ; Atopic Dermatitis and Skin Disease ; Biological and medical sciences ; Child ; Child, Preschool ; confocal Raman spectroscopy ; Cytokines - metabolism ; Dermatitis, Atopic - genetics ; Dermatitis, Atopic - metabolism ; eczema ; Enzymes ; Families & family life ; Female ; Filaggrin ; FLG gene mutations ; Flgft/Flgft (FlgdelAPfal) mice ; Fundamental and applied biological sciences. Psychology ; Fundamental immunology ; Genotype ; Genotype & phenotype ; Homeostasis ; Humans ; Hydrogen-Ion Concentration ; Hypotheses ; IL-1 ; IL-18 ; Immunopathology ; Infant ; Inflammation ; Interleukin 1 ; Interleukin 1 receptor antagonist ; Interleukin 18 ; Interleukin 8 ; Interleukin-1 - genetics ; Interleukin-1 - metabolism ; Intermediate Filament Proteins - genetics ; Intermediate Filament Proteins - metabolism ; Keratinocytes ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; mRNA ; Mutation ; natural moisturizing factor ; pH effects ; Polymerase chain reaction ; Primers ; Proteinase ; Proteins ; Raman spectroscopy ; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis ; Skin ; Skin - metabolism ; Skin allergic diseases. Stinging insect allergies ; skin barrier ; Stratum corneum ; Tails ; transepidermal water loss ; Values ; Water loss</subject><ispartof>Journal of allergy and clinical immunology, 2012-04, Vol.129 (4), p.1031-1039.e1</ispartof><rights>American Academy of Allergy, Asthma & Immunology</rights><rights>2012 American Academy of Allergy, Asthma & Immunology</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Apr 2012</rights><rights>2012 Mosby, Inc. 2012 American Academy of Allergy, Asthma & Immunology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c600t-20cc98f294c3093acaed7f538a98e8abae487bd1cd1dfd28276dc00dd4928ec73</citedby><cites>FETCH-LOGICAL-c600t-20cc98f294c3093acaed7f538a98e8abae487bd1cd1dfd28276dc00dd4928ec73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0091674911029587$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25754283$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22322004$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kezic, Sanja, PhD</creatorcontrib><creatorcontrib>O’Regan, Gráinne M., MRCPI</creatorcontrib><creatorcontrib>Lutter, René, PhD</creatorcontrib><creatorcontrib>Jakasa, Ivone, PhD</creatorcontrib><creatorcontrib>Koster, Ellen S., PhD</creatorcontrib><creatorcontrib>Saunders, Sean, BSc</creatorcontrib><creatorcontrib>Caspers, Peter, PhD</creatorcontrib><creatorcontrib>Kemperman, Patrick M.J.H., MD</creatorcontrib><creatorcontrib>Puppels, Gerwin J., PhD</creatorcontrib><creatorcontrib>Sandilands, Aileen, PhD</creatorcontrib><creatorcontrib>Chen, Huijia, PhD</creatorcontrib><creatorcontrib>Campbell, Linda E., BSc</creatorcontrib><creatorcontrib>Kroboth, Karin, MSc</creatorcontrib><creatorcontrib>Watson, Rosemarie, MD</creatorcontrib><creatorcontrib>Fallon, Padraic G., PhD</creatorcontrib><creatorcontrib>McLean, W. H. Irwin, DSc, FMedSci</creatorcontrib><creatorcontrib>Irvine, Alan D., MD, FRCPI</creatorcontrib><title>Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>Background Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD FLG ) compared with that seen in patients with AD without these mutations (AD NON-FLG ). Objectives We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD FLG versus patients with AD NON-FLG . We also sought to examine the same profiles in a murine model of filaggrin deficiency ( Flgft /Flgft [ FlgdelAPfal ] mice). Methods One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1α, IL-1β, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flgft /Flgft (FlgdelAPfal ) mice, separated from maFlgft /maFlgft (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1α, IL-1β, and IL-1RA. Results SC IL-1 levels were increased in patients with AD FLG ; these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flgft /Flgft mice had upregulated expression of IL-1β and IL-1RA mRNA. Conclusions AD FLG is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches.</description><subject>Adolescent</subject><subject>Alleles</subject><subject>Allergic diseases</subject><subject>Allergy and Immunology</subject><subject>Animal models</subject><subject>Animals</subject><subject>Atopic dermatitis</subject><subject>Atopic Dermatitis and Skin Disease</subject><subject>Biological and medical sciences</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>confocal Raman spectroscopy</subject><subject>Cytokines - metabolism</subject><subject>Dermatitis, Atopic - genetics</subject><subject>Dermatitis, Atopic - metabolism</subject><subject>eczema</subject><subject>Enzymes</subject><subject>Families & family life</subject><subject>Female</subject><subject>Filaggrin</subject><subject>FLG gene mutations</subject><subject>Flgft/Flgft (FlgdelAPfal) mice</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Fundamental immunology</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Hypotheses</subject><subject>IL-1</subject><subject>IL-18</subject><subject>Immunopathology</subject><subject>Infant</subject><subject>Inflammation</subject><subject>Interleukin 1</subject><subject>Interleukin 1 receptor antagonist</subject><subject>Interleukin 18</subject><subject>Interleukin 8</subject><subject>Interleukin-1 - genetics</subject><subject>Interleukin-1 - metabolism</subject><subject>Intermediate Filament Proteins - genetics</subject><subject>Intermediate Filament Proteins - metabolism</subject><subject>Keratinocytes</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>mRNA</subject><subject>Mutation</subject><subject>natural moisturizing factor</subject><subject>pH effects</subject><subject>Polymerase chain reaction</subject><subject>Primers</subject><subject>Proteinase</subject><subject>Proteins</subject><subject>Raman spectroscopy</subject><subject>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</subject><subject>Skin</subject><subject>Skin - metabolism</subject><subject>Skin allergic diseases. Stinging insect allergies</subject><subject>skin barrier</subject><subject>Stratum corneum</subject><subject>Tails</subject><subject>transepidermal water loss</subject><subject>Values</subject><subject>Water loss</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9ks1u1DAUhSMEoqXwAiyQJYRgk8F2_mwJVUIVhUojsQDWlmvfdDxN7MF2CvOCPBc3zDCFLrpy7Hzn-F7fUxTPGV0wytq368VaG7fglLEF4wsp5IPimFHZla3gzcPimFLJyrar5VHxJKU1xX0l5OPiiPOKc0rr4-LXuRv01VV0ngwhpTL0ZT95k13wZJyynj8S0RGITikYpzNY8sPlFQG_0t7gDn5uIqQ0K0JPLpYlI2abw7XzkAj65hWQlKPO00hMiB5wRXCD3uBz2rnpHDbOEAtxxPPs8E5vZ7XGMrA6IGOwMMzC_lCxhd4ZNDHbp8WjXg8Jnu3Xk-Lb-YevZ5_K5eePF2fvl6VpKc0lp8ZI0XNZmwrfQhsNtuubSmgpQOhLDbXoLi0zltnecsG71hpKra0lF2C66qQ43flupssRrMEGoh7UJrpRx60K2qn__3i3UlfhRlUt72Qj0eD13iCG7xOkrEaXDAyD9hCmpGRbiQqnK5B8cy-JEOOs6yqO6Ms76DpM0eNDKNbUnWilELMh31Em4qQj9IeyGZ3dWrVWc6DUHCjFuMJAoejFvw0fJH8ThMCrPaCT0UMfMRQu3XJN19RcVMi923GA47lxEFX6MzqwLoLJygZ3fx2nd-RmcN7hjdewhXTbr0pcUfVljv6cfMYol43oqt9B4QP3</recordid><startdate>20120401</startdate><enddate>20120401</enddate><creator>Kezic, Sanja, PhD</creator><creator>O’Regan, Gráinne M., MRCPI</creator><creator>Lutter, René, PhD</creator><creator>Jakasa, Ivone, PhD</creator><creator>Koster, Ellen S., PhD</creator><creator>Saunders, Sean, BSc</creator><creator>Caspers, Peter, PhD</creator><creator>Kemperman, Patrick M.J.H., MD</creator><creator>Puppels, Gerwin J., PhD</creator><creator>Sandilands, Aileen, PhD</creator><creator>Chen, Huijia, PhD</creator><creator>Campbell, Linda E., BSc</creator><creator>Kroboth, Karin, MSc</creator><creator>Watson, Rosemarie, MD</creator><creator>Fallon, Padraic G., PhD</creator><creator>McLean, W. 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Irwin, DSc, FMedSci</creator><creator>Irvine, Alan D., MD, FRCPI</creator><general>Elsevier Inc</general><general>Elsevier</general><general>Elsevier Limited</general><general>Mosby</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120401</creationdate><title>Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency</title><author>Kezic, Sanja, PhD ; O’Regan, Gráinne M., MRCPI ; Lutter, René, PhD ; Jakasa, Ivone, PhD ; Koster, Ellen S., PhD ; Saunders, Sean, BSc ; Caspers, Peter, PhD ; Kemperman, Patrick M.J.H., MD ; Puppels, Gerwin J., PhD ; Sandilands, Aileen, PhD ; Chen, Huijia, PhD ; Campbell, Linda E., BSc ; Kroboth, Karin, MSc ; Watson, Rosemarie, MD ; Fallon, Padraic G., PhD ; McLean, W. 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Irwin, DSc, FMedSci ; Irvine, Alan D., MD, FRCPI</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c600t-20cc98f294c3093acaed7f538a98e8abae487bd1cd1dfd28276dc00dd4928ec73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adolescent</topic><topic>Alleles</topic><topic>Allergic diseases</topic><topic>Allergy and Immunology</topic><topic>Animal models</topic><topic>Animals</topic><topic>Atopic dermatitis</topic><topic>Atopic Dermatitis and Skin Disease</topic><topic>Biological and medical sciences</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>confocal Raman spectroscopy</topic><topic>Cytokines - metabolism</topic><topic>Dermatitis, Atopic - genetics</topic><topic>Dermatitis, Atopic - metabolism</topic><topic>eczema</topic><topic>Enzymes</topic><topic>Families & family life</topic><topic>Female</topic><topic>Filaggrin</topic><topic>FLG gene mutations</topic><topic>Flgft/Flgft (FlgdelAPfal) mice</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Fundamental immunology</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Hypotheses</topic><topic>IL-1</topic><topic>IL-18</topic><topic>Immunopathology</topic><topic>Infant</topic><topic>Inflammation</topic><topic>Interleukin 1</topic><topic>Interleukin 1 receptor antagonist</topic><topic>Interleukin 18</topic><topic>Interleukin 8</topic><topic>Interleukin-1 - genetics</topic><topic>Interleukin-1 - metabolism</topic><topic>Intermediate Filament Proteins - genetics</topic><topic>Intermediate Filament Proteins - metabolism</topic><topic>Keratinocytes</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>mRNA</topic><topic>Mutation</topic><topic>natural moisturizing factor</topic><topic>pH effects</topic><topic>Polymerase chain reaction</topic><topic>Primers</topic><topic>Proteinase</topic><topic>Proteins</topic><topic>Raman spectroscopy</topic><topic>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</topic><topic>Skin</topic><topic>Skin - metabolism</topic><topic>Skin allergic diseases. Stinging insect allergies</topic><topic>skin barrier</topic><topic>Stratum corneum</topic><topic>Tails</topic><topic>transepidermal water loss</topic><topic>Values</topic><topic>Water loss</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kezic, Sanja, PhD</creatorcontrib><creatorcontrib>O’Regan, Gráinne M., MRCPI</creatorcontrib><creatorcontrib>Lutter, René, PhD</creatorcontrib><creatorcontrib>Jakasa, Ivone, PhD</creatorcontrib><creatorcontrib>Koster, Ellen S., PhD</creatorcontrib><creatorcontrib>Saunders, Sean, BSc</creatorcontrib><creatorcontrib>Caspers, Peter, PhD</creatorcontrib><creatorcontrib>Kemperman, Patrick M.J.H., MD</creatorcontrib><creatorcontrib>Puppels, Gerwin J., PhD</creatorcontrib><creatorcontrib>Sandilands, Aileen, PhD</creatorcontrib><creatorcontrib>Chen, Huijia, PhD</creatorcontrib><creatorcontrib>Campbell, Linda E., BSc</creatorcontrib><creatorcontrib>Kroboth, Karin, MSc</creatorcontrib><creatorcontrib>Watson, Rosemarie, MD</creatorcontrib><creatorcontrib>Fallon, Padraic G., PhD</creatorcontrib><creatorcontrib>McLean, W. H. Irwin, DSc, FMedSci</creatorcontrib><creatorcontrib>Irvine, Alan D., MD, FRCPI</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kezic, Sanja, PhD</au><au>O’Regan, Gráinne M., MRCPI</au><au>Lutter, René, PhD</au><au>Jakasa, Ivone, PhD</au><au>Koster, Ellen S., PhD</au><au>Saunders, Sean, BSc</au><au>Caspers, Peter, PhD</au><au>Kemperman, Patrick M.J.H., MD</au><au>Puppels, Gerwin J., PhD</au><au>Sandilands, Aileen, PhD</au><au>Chen, Huijia, PhD</au><au>Campbell, Linda E., BSc</au><au>Kroboth, Karin, MSc</au><au>Watson, Rosemarie, MD</au><au>Fallon, Padraic G., PhD</au><au>McLean, W. H. Irwin, DSc, FMedSci</au><au>Irvine, Alan D., MD, FRCPI</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2012-04-01</date><risdate>2012</risdate><volume>129</volume><issue>4</issue><spage>1031</spage><epage>1039.e1</epage><pages>1031-1039.e1</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><coden>JACIBY</coden><abstract>Background Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD FLG ) compared with that seen in patients with AD without these mutations (AD NON-FLG ). Objectives We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD FLG versus patients with AD NON-FLG . We also sought to examine the same profiles in a murine model of filaggrin deficiency ( Flgft /Flgft [ FlgdelAPfal ] mice). Methods One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1α, IL-1β, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flgft /Flgft (FlgdelAPfal ) mice, separated from maFlgft /maFlgft (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1α, IL-1β, and IL-1RA. Results SC IL-1 levels were increased in patients with AD FLG ; these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flgft /Flgft mice had upregulated expression of IL-1β and IL-1RA mRNA. Conclusions AD FLG is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>22322004</pmid><doi>10.1016/j.jaci.2011.12.989</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0091-6749 |
| ispartof | Journal of allergy and clinical immunology, 2012-04, Vol.129 (4), p.1031-1039.e1 |
| issn | 0091-6749 1097-6825 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3627959 |
| source | MEDLINE; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adolescent Alleles Allergic diseases Allergy and Immunology Animal models Animals Atopic dermatitis Atopic Dermatitis and Skin Disease Biological and medical sciences Child Child, Preschool confocal Raman spectroscopy Cytokines - metabolism Dermatitis, Atopic - genetics Dermatitis, Atopic - metabolism eczema Enzymes Families & family life Female Filaggrin FLG gene mutations Flgft/Flgft (FlgdelAPfal) mice Fundamental and applied biological sciences. Psychology Fundamental immunology Genotype Genotype & phenotype Homeostasis Humans Hydrogen-Ion Concentration Hypotheses IL-1 IL-18 Immunopathology Infant Inflammation Interleukin 1 Interleukin 1 receptor antagonist Interleukin 18 Interleukin 8 Interleukin-1 - genetics Interleukin-1 - metabolism Intermediate Filament Proteins - genetics Intermediate Filament Proteins - metabolism Keratinocytes Male Medical sciences Mice Mice, Inbred C57BL Mice, Knockout mRNA Mutation natural moisturizing factor pH effects Polymerase chain reaction Primers Proteinase Proteins Raman spectroscopy Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis Skin Skin - metabolism Skin allergic diseases. Stinging insect allergies skin barrier Stratum corneum Tails transepidermal water loss Values Water loss |
| title | Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency |
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