Heparinoid suppresses Der p‐induced IL‐1β production by inhibiting ERK and p38 MAPK pathways in keratinocytes
Epidermal keratinocytes initiate skin inflammation by activating immune cells. The skin barrier is disrupted in atopic dermatitis (AD) and epidermal keratinocytes can be exposed to environmental stimuli, such as house dust mite (HDM) allergens. We showed previously that HDM allergens activate the NL...
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| Veröffentlicht in: | Experimental dermatology 2018-09, Vol.27 (9), p.981-988 |
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| creator | Utsunomiya, Ryo Dai, Xiuju Murakami, Masamoto Masuda, Kana Okazaki, Hidenori Tsuda, Teruko Mori, Hideki Shiraishi, Ken Tohyama, Mikiko Sayama, Koji |
| description | Epidermal keratinocytes initiate skin inflammation by activating immune cells. The skin barrier is disrupted in atopic dermatitis (AD) and epidermal keratinocytes can be exposed to environmental stimuli, such as house dust mite (HDM) allergens. We showed previously that HDM allergens activate the NLRP3 inflammasome of keratinocytes, thereby releasing pro‐inflammatory cytokines. Heparinoid is an effective moisturizer for atopic dry skin. However, a recent report showed that heparinoid treatment can improve inflammation of lichen planus. Therefore, we hypothesized that it acts on epidermal keratinocytes not only as a moisturizer, but also as a suppressant of the triggers of skin inflammation. We found that HDM allergen‐induced interleukin (IL)‐1β release from keratinocytes was inhibited significantly by heparinoid pretreatment without affecting cell viability. However, heparinoid did not affect caspase‐1 release, suggesting that heparinoid did not affect HDM allergen‐induced inflammasome activation. Heparinoid treatment not only decreased intracellular levels of pro‐IL‐1β, but also suppressed IL‐1β messenger RNA (mRNA) expression in keratinocytes. Among the intracellular signalling pathways, the activation of extracellular signal‐regulated kinase and p38 pathways, which are required for IL‐1β expression in keratinocytes, was inhibited by heparinoid treatment. The inhibitory effect of heparinoid on IL‐1β mRNA expression was also confirmed with living skin equivalents. Our results demonstrated that heparinoid suppresses the initiation of keratinocyte‐mediated skin inflammation. |
| doi_str_mv | 10.1111/exd.13685 |
| format | Article |
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The skin barrier is disrupted in atopic dermatitis (AD) and epidermal keratinocytes can be exposed to environmental stimuli, such as house dust mite (HDM) allergens. We showed previously that HDM allergens activate the NLRP3 inflammasome of keratinocytes, thereby releasing pro‐inflammatory cytokines. Heparinoid is an effective moisturizer for atopic dry skin. However, a recent report showed that heparinoid treatment can improve inflammation of lichen planus. Therefore, we hypothesized that it acts on epidermal keratinocytes not only as a moisturizer, but also as a suppressant of the triggers of skin inflammation. We found that HDM allergen‐induced interleukin (IL)‐1β release from keratinocytes was inhibited significantly by heparinoid pretreatment without affecting cell viability. However, heparinoid did not affect caspase‐1 release, suggesting that heparinoid did not affect HDM allergen‐induced inflammasome activation. Heparinoid treatment not only decreased intracellular levels of pro‐IL‐1β, but also suppressed IL‐1β messenger RNA (mRNA) expression in keratinocytes. Among the intracellular signalling pathways, the activation of extracellular signal‐regulated kinase and p38 pathways, which are required for IL‐1β expression in keratinocytes, was inhibited by heparinoid treatment. The inhibitory effect of heparinoid on IL‐1β mRNA expression was also confirmed with living skin equivalents. Our results demonstrated that heparinoid suppresses the initiation of keratinocyte‐mediated skin inflammation.</description><identifier>ISSN: 0906-6705</identifier><identifier>EISSN: 1600-0625</identifier><identifier>DOI: 10.1111/exd.13685</identifier><identifier>PMID: 29754454</identifier><language>eng</language><publisher>Denmark: Wiley Subscription Services, Inc</publisher><subject>Allergens ; Allergies ; Antigens, Dermatophagoides - pharmacology ; Atopic dermatitis ; Caspase ; Caspase 1 - metabolism ; Dermatitis ; Environmental effects ; ERK ; Extracellular signal-regulated kinase ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Gene expression ; Gene Expression - drug effects ; Heparinoid ; Heparinoids - pharmacology ; Humans ; IL-1β ; Infant ; Inflammasomes ; Inflammation ; Interleukin-1beta - genetics ; Interleukin-1beta - metabolism ; Interleukin-8 - metabolism ; Intracellular ; Intracellular levels ; Intracellular signalling ; Keratinocytes ; Keratinocytes - metabolism ; Lichen planus ; MAP kinase ; p38 ; p38 Mitogen-Activated Protein Kinases - metabolism ; Primary Cell Culture ; RNA, Messenger - metabolism ; Signal transduction ; Signal Transduction - drug effects ; Skin ; Toll-Like Receptor 2 - genetics ; Toll-Like Receptor 4 - genetics ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>Experimental dermatology, 2018-09, Vol.27 (9), p.981-988</ispartof><rights>2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><rights>2018 John Wiley & Sons A/S. 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The skin barrier is disrupted in atopic dermatitis (AD) and epidermal keratinocytes can be exposed to environmental stimuli, such as house dust mite (HDM) allergens. We showed previously that HDM allergens activate the NLRP3 inflammasome of keratinocytes, thereby releasing pro‐inflammatory cytokines. Heparinoid is an effective moisturizer for atopic dry skin. However, a recent report showed that heparinoid treatment can improve inflammation of lichen planus. Therefore, we hypothesized that it acts on epidermal keratinocytes not only as a moisturizer, but also as a suppressant of the triggers of skin inflammation. We found that HDM allergen‐induced interleukin (IL)‐1β release from keratinocytes was inhibited significantly by heparinoid pretreatment without affecting cell viability. However, heparinoid did not affect caspase‐1 release, suggesting that heparinoid did not affect HDM allergen‐induced inflammasome activation. Heparinoid treatment not only decreased intracellular levels of pro‐IL‐1β, but also suppressed IL‐1β messenger RNA (mRNA) expression in keratinocytes. Among the intracellular signalling pathways, the activation of extracellular signal‐regulated kinase and p38 pathways, which are required for IL‐1β expression in keratinocytes, was inhibited by heparinoid treatment. The inhibitory effect of heparinoid on IL‐1β mRNA expression was also confirmed with living skin equivalents. Our results demonstrated that heparinoid suppresses the initiation of keratinocyte‐mediated skin inflammation.</description><subject>Allergens</subject><subject>Allergies</subject><subject>Antigens, Dermatophagoides - pharmacology</subject><subject>Atopic dermatitis</subject><subject>Caspase</subject><subject>Caspase 1 - metabolism</subject><subject>Dermatitis</subject><subject>Environmental effects</subject><subject>ERK</subject><subject>Extracellular signal-regulated kinase</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Heparinoid</subject><subject>Heparinoids - pharmacology</subject><subject>Humans</subject><subject>IL-1β</subject><subject>Infant</subject><subject>Inflammasomes</subject><subject>Inflammation</subject><subject>Interleukin-1beta - genetics</subject><subject>Interleukin-1beta - metabolism</subject><subject>Interleukin-8 - metabolism</subject><subject>Intracellular</subject><subject>Intracellular levels</subject><subject>Intracellular signalling</subject><subject>Keratinocytes</subject><subject>Keratinocytes - metabolism</subject><subject>Lichen planus</subject><subject>MAP kinase</subject><subject>p38</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Primary Cell Culture</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Skin</subject><subject>Toll-Like Receptor 2 - genetics</subject><subject>Toll-Like Receptor 4 - genetics</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0906-6705</issn><issn>1600-0625</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp10U1O3DAYBmALFcHws-AClaVu6CLgf8dLBFNADAKhVuoucpwvxTCTBDsRZMcROAsH4RA9SV2GdoGEN5atR68-fS9CO5Ts0XT24aHao1zlcgVNqCIkI4rJT2hCDFGZ0kSuo40Ybwihmmu5htaZ0VIIKSYonEBng29aX-E4dF2AGCHiIwi4-_345JtqcFDh01l60Jdn3IU2_fS-bXA5Yt9c-9L3vvmFp1dn2DYV7niOzw8uz3Bn--t7O8aE8C0Em1Trxh7iFlqt7TzC9tu9iX58m34_PMlmF8enhwezzHHJZKbA5EIoLWotlFVWakm0NMIZVpdQgS6ddkBrqnJHuBHKCcoqnnNJhGPC8U20u8xNM98NEPti4aOD-dw20A6xYITnmoic8kS_vKM37RCaNF1SRgrGmTFJfV0qF9oYA9RFF_zChrGgpPhbRJGKKF6LSPbzW-JQLqD6L_9tPoH9Jbj3cxg_TiqmP4-WkX8AFzOTBw</recordid><startdate>201809</startdate><enddate>201809</enddate><creator>Utsunomiya, Ryo</creator><creator>Dai, Xiuju</creator><creator>Murakami, Masamoto</creator><creator>Masuda, Kana</creator><creator>Okazaki, Hidenori</creator><creator>Tsuda, Teruko</creator><creator>Mori, Hideki</creator><creator>Shiraishi, Ken</creator><creator>Tohyama, Mikiko</creator><creator>Sayama, Koji</creator><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</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>7T5</scope><scope>H94</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7257-5784</orcidid><orcidid>https://orcid.org/0000-0002-1487-7466</orcidid></search><sort><creationdate>201809</creationdate><title>Heparinoid suppresses Der p‐induced IL‐1β production by inhibiting ERK and p38 MAPK pathways in keratinocytes</title><author>Utsunomiya, Ryo ; Dai, Xiuju ; Murakami, Masamoto ; Masuda, Kana ; Okazaki, Hidenori ; Tsuda, Teruko ; Mori, Hideki ; Shiraishi, Ken ; Tohyama, Mikiko ; Sayama, Koji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3525-6e9844674f746a6a57507594c92fbede7bc7ce1f168c03946c412d383504c24c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Allergens</topic><topic>Allergies</topic><topic>Antigens, Dermatophagoides - pharmacology</topic><topic>Atopic dermatitis</topic><topic>Caspase</topic><topic>Caspase 1 - metabolism</topic><topic>Dermatitis</topic><topic>Environmental effects</topic><topic>ERK</topic><topic>Extracellular signal-regulated kinase</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Gene expression</topic><topic>Gene Expression - drug effects</topic><topic>Heparinoid</topic><topic>Heparinoids - pharmacology</topic><topic>Humans</topic><topic>IL-1β</topic><topic>Infant</topic><topic>Inflammasomes</topic><topic>Inflammation</topic><topic>Interleukin-1beta - genetics</topic><topic>Interleukin-1beta - metabolism</topic><topic>Interleukin-8 - metabolism</topic><topic>Intracellular</topic><topic>Intracellular levels</topic><topic>Intracellular signalling</topic><topic>Keratinocytes</topic><topic>Keratinocytes - metabolism</topic><topic>Lichen planus</topic><topic>MAP kinase</topic><topic>p38</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>Primary Cell Culture</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Skin</topic><topic>Toll-Like Receptor 2 - genetics</topic><topic>Toll-Like Receptor 4 - genetics</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Utsunomiya, Ryo</creatorcontrib><creatorcontrib>Dai, Xiuju</creatorcontrib><creatorcontrib>Murakami, Masamoto</creatorcontrib><creatorcontrib>Masuda, Kana</creatorcontrib><creatorcontrib>Okazaki, Hidenori</creatorcontrib><creatorcontrib>Tsuda, Teruko</creatorcontrib><creatorcontrib>Mori, Hideki</creatorcontrib><creatorcontrib>Shiraishi, Ken</creatorcontrib><creatorcontrib>Tohyama, Mikiko</creatorcontrib><creatorcontrib>Sayama, Koji</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental dermatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Utsunomiya, Ryo</au><au>Dai, Xiuju</au><au>Murakami, Masamoto</au><au>Masuda, Kana</au><au>Okazaki, Hidenori</au><au>Tsuda, Teruko</au><au>Mori, Hideki</au><au>Shiraishi, Ken</au><au>Tohyama, Mikiko</au><au>Sayama, Koji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Heparinoid suppresses Der p‐induced IL‐1β production by inhibiting ERK and p38 MAPK pathways in keratinocytes</atitle><jtitle>Experimental dermatology</jtitle><addtitle>Exp Dermatol</addtitle><date>2018-09</date><risdate>2018</risdate><volume>27</volume><issue>9</issue><spage>981</spage><epage>988</epage><pages>981-988</pages><issn>0906-6705</issn><eissn>1600-0625</eissn><abstract>Epidermal keratinocytes initiate skin inflammation by activating immune cells. The skin barrier is disrupted in atopic dermatitis (AD) and epidermal keratinocytes can be exposed to environmental stimuli, such as house dust mite (HDM) allergens. We showed previously that HDM allergens activate the NLRP3 inflammasome of keratinocytes, thereby releasing pro‐inflammatory cytokines. Heparinoid is an effective moisturizer for atopic dry skin. However, a recent report showed that heparinoid treatment can improve inflammation of lichen planus. Therefore, we hypothesized that it acts on epidermal keratinocytes not only as a moisturizer, but also as a suppressant of the triggers of skin inflammation. We found that HDM allergen‐induced interleukin (IL)‐1β release from keratinocytes was inhibited significantly by heparinoid pretreatment without affecting cell viability. However, heparinoid did not affect caspase‐1 release, suggesting that heparinoid did not affect HDM allergen‐induced inflammasome activation. Heparinoid treatment not only decreased intracellular levels of pro‐IL‐1β, but also suppressed IL‐1β messenger RNA (mRNA) expression in keratinocytes. Among the intracellular signalling pathways, the activation of extracellular signal‐regulated kinase and p38 pathways, which are required for IL‐1β expression in keratinocytes, was inhibited by heparinoid treatment. The inhibitory effect of heparinoid on IL‐1β mRNA expression was also confirmed with living skin equivalents. Our results demonstrated that heparinoid suppresses the initiation of keratinocyte‐mediated skin inflammation.</abstract><cop>Denmark</cop><pub>Wiley Subscription Services, Inc</pub><pmid>29754454</pmid><doi>10.1111/exd.13685</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-7257-5784</orcidid><orcidid>https://orcid.org/0000-0002-1487-7466</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Allergens Allergies Antigens, Dermatophagoides - pharmacology Atopic dermatitis Caspase Caspase 1 - metabolism Dermatitis Environmental effects ERK Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases - metabolism Gene expression Gene Expression - drug effects Heparinoid Heparinoids - pharmacology Humans IL-1β Infant Inflammasomes Inflammation Interleukin-1beta - genetics Interleukin-1beta - metabolism Interleukin-8 - metabolism Intracellular Intracellular levels Intracellular signalling Keratinocytes Keratinocytes - metabolism Lichen planus MAP kinase p38 p38 Mitogen-Activated Protein Kinases - metabolism Primary Cell Culture RNA, Messenger - metabolism Signal transduction Signal Transduction - drug effects Skin Toll-Like Receptor 2 - genetics Toll-Like Receptor 4 - genetics Tumor Necrosis Factor-alpha - metabolism |
| title | Heparinoid suppresses Der p‐induced IL‐1β production by inhibiting ERK and p38 MAPK pathways in keratinocytes |
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