Expression of functional leukotriene B4 receptors on human airway smooth muscle cells
Background Leukotriene B4 (LTB4 ) increases in induced sputum and exhaled breath condensate in people with asthma. Furthermore, the TH 2-type immune response and airway hyperresponsiveness induced by ovalbumin sensitization is markedly suppressed in LTB4 receptor (BLT) 1 null mice. These studies sug...
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| creator | Watanabe, Satoko, BS Yamasaki, Akira, MD, PhD Hashimoto, Kiyoshi, MD, PhD Shigeoka, Yasushi, MD, PhD Chikumi, Hiroki, MD, PhD Hasegawa, Yasuyuki, MD, PhD Sumikawa, Takashi, MD, PhD Takata, Miyako, PhD Okazaki, Ryota, MD Watanabe, Masanari, MD, PhD Yokogawa, Tsuyoshi, BS Yamamura, Miki, MD Hayabuchi, Tatsuya, MD Gerthoffer, William T., PhD Halayko, Andrew J., PhD Shimizu, Eiji, MD, PhD |
| description | Background Leukotriene B4 (LTB4 ) increases in induced sputum and exhaled breath condensate in people with asthma. Furthermore, the TH 2-type immune response and airway hyperresponsiveness induced by ovalbumin sensitization is markedly suppressed in LTB4 receptor (BLT) 1 null mice. These studies suggest that LTB4 may contribute to asthma pathophysiology. However, the direct effects of LTB4 on human airway smooth muscle (ASM) have not been studied. Objectives We sought to determine the expression of LTB4 receptors on human ASM and its functional role in mediating responses of human ASM cells, and the effect of LTB4 on these cells. Methods Immunohistochemistry, RT-PCR, Western blotting, and flow cytometry were used to determine the expression of LTB4 receptors. To determine the effect of LTB4 on human ASM cells, cell proliferation was assessed by counting cells, and chemokinesis was assessed by gold particle phagokinesis assay. Results We confirmed expression of both BLT1 and BLT2 in human ASM cells in bronchial tissue and in cell culture. LTB4 markedly induced cyclin D1 expression, proliferation, and chemokinesis of human ASM cells. LTB4 also induced phosphorylation of both p42/p44 mitogen-activated protein kinase (MAPK) and downstream PI3 kinase effector, Akt1. However, we observed no induction of c-Jun N-terminal kinase or p38 MAPK. Notably, LTB4 -induced migration and proliferation of ASM cells were inhibited by the BLT1 specific antagonist, U75302, and by inhibitors of p42/p44 MAPK phosphorylation (U1026), and PI3 kinase (LY294002). Conclusions These observations are the first to suggest a role for a LTB4 -BLT1 signaling axis in ASM responses that may contribute to the pathogenesis of airway remodeling in asthma. |
| doi_str_mv | 10.1016/j.jaci.2009.03.024 |
| format | Article |
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Furthermore, the TH 2-type immune response and airway hyperresponsiveness induced by ovalbumin sensitization is markedly suppressed in LTB4 receptor (BLT) 1 null mice. These studies suggest that LTB4 may contribute to asthma pathophysiology. However, the direct effects of LTB4 on human airway smooth muscle (ASM) have not been studied. Objectives We sought to determine the expression of LTB4 receptors on human ASM and its functional role in mediating responses of human ASM cells, and the effect of LTB4 on these cells. Methods Immunohistochemistry, RT-PCR, Western blotting, and flow cytometry were used to determine the expression of LTB4 receptors. To determine the effect of LTB4 on human ASM cells, cell proliferation was assessed by counting cells, and chemokinesis was assessed by gold particle phagokinesis assay. Results We confirmed expression of both BLT1 and BLT2 in human ASM cells in bronchial tissue and in cell culture. LTB4 markedly induced cyclin D1 expression, proliferation, and chemokinesis of human ASM cells. LTB4 also induced phosphorylation of both p42/p44 mitogen-activated protein kinase (MAPK) and downstream PI3 kinase effector, Akt1. However, we observed no induction of c-Jun N-terminal kinase or p38 MAPK. Notably, LTB4 -induced migration and proliferation of ASM cells were inhibited by the BLT1 specific antagonist, U75302, and by inhibitors of p42/p44 MAPK phosphorylation (U1026), and PI3 kinase (LY294002). Conclusions These observations are the first to suggest a role for a LTB4 -BLT1 signaling axis in ASM responses that may contribute to the pathogenesis of airway remodeling in asthma.</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2009.03.024</identifier><identifier>PMID: 19477492</identifier><identifier>CODEN: JACIBY</identifier><language>eng</language><publisher>New York, NY: Elsevier</publisher><subject>Allergy and Immunology ; Biological and medical sciences ; Blotting, Western ; Bronchi - immunology ; Bronchi - metabolism ; Cell cycle ; Cell Line ; Cell Movement ; Cell Proliferation ; Chronic obstructive pulmonary disease, asthma ; Cyclin-Dependent Kinases - metabolism ; Dehydrogenases ; Epidermal growth factor ; Flow cytometry ; Fundamental and applied biological sciences. Psychology ; Fundamental immunology ; Gene Expression Regulation ; Humans ; Immunohistochemistry ; Immunopathology ; Kinases ; Medical sciences ; Mitogen-Activated Protein Kinase 3 - metabolism ; Muscular system ; Myocytes, Smooth Muscle - immunology ; Myocytes, Smooth Muscle - metabolism ; Phosphorylation ; Pneumology ; Polyclonal antibodies ; Proteins ; Receptors, Leukotriene B4 - genetics ; Receptors, Leukotriene B4 - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - metabolism ; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis ; Signal Transduction ; Smooth muscle</subject><ispartof>Journal of allergy and clinical immunology, 2009-07, Vol.124 (1), p.59-65.e3</ispartof><rights>American Academy of Allergy, Asthma & Immunology</rights><rights>2009 INIST-CNRS</rights><rights>Copyright Elsevier Limited Jul 2009</rights><rights>2009 American Academy of Allergy, Asthma & Immunology 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4944-a638ac1cf167e33b76ae3176d10d610fcd1d984fa8cf28ae4fd34188e59268da3</citedby><cites>FETCH-LOGICAL-c4944-a638ac1cf167e33b76ae3176d10d610fcd1d984fa8cf28ae4fd34188e59268da3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21699092$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19477492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Watanabe, Satoko, BS</creatorcontrib><creatorcontrib>Yamasaki, Akira, MD, PhD</creatorcontrib><creatorcontrib>Hashimoto, Kiyoshi, MD, PhD</creatorcontrib><creatorcontrib>Shigeoka, Yasushi, MD, PhD</creatorcontrib><creatorcontrib>Chikumi, Hiroki, MD, PhD</creatorcontrib><creatorcontrib>Hasegawa, Yasuyuki, MD, PhD</creatorcontrib><creatorcontrib>Sumikawa, Takashi, MD, PhD</creatorcontrib><creatorcontrib>Takata, Miyako, PhD</creatorcontrib><creatorcontrib>Okazaki, Ryota, MD</creatorcontrib><creatorcontrib>Watanabe, Masanari, MD, PhD</creatorcontrib><creatorcontrib>Yokogawa, Tsuyoshi, BS</creatorcontrib><creatorcontrib>Yamamura, Miki, MD</creatorcontrib><creatorcontrib>Hayabuchi, Tatsuya, MD</creatorcontrib><creatorcontrib>Gerthoffer, William T., PhD</creatorcontrib><creatorcontrib>Halayko, Andrew J., PhD</creatorcontrib><creatorcontrib>Shimizu, Eiji, MD, PhD</creatorcontrib><title>Expression of functional leukotriene B4 receptors on human airway smooth muscle cells</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>Background Leukotriene B4 (LTB4 ) increases in induced sputum and exhaled breath condensate in people with asthma. Furthermore, the TH 2-type immune response and airway hyperresponsiveness induced by ovalbumin sensitization is markedly suppressed in LTB4 receptor (BLT) 1 null mice. These studies suggest that LTB4 may contribute to asthma pathophysiology. However, the direct effects of LTB4 on human airway smooth muscle (ASM) have not been studied. Objectives We sought to determine the expression of LTB4 receptors on human ASM and its functional role in mediating responses of human ASM cells, and the effect of LTB4 on these cells. Methods Immunohistochemistry, RT-PCR, Western blotting, and flow cytometry were used to determine the expression of LTB4 receptors. To determine the effect of LTB4 on human ASM cells, cell proliferation was assessed by counting cells, and chemokinesis was assessed by gold particle phagokinesis assay. Results We confirmed expression of both BLT1 and BLT2 in human ASM cells in bronchial tissue and in cell culture. LTB4 markedly induced cyclin D1 expression, proliferation, and chemokinesis of human ASM cells. LTB4 also induced phosphorylation of both p42/p44 mitogen-activated protein kinase (MAPK) and downstream PI3 kinase effector, Akt1. However, we observed no induction of c-Jun N-terminal kinase or p38 MAPK. Notably, LTB4 -induced migration and proliferation of ASM cells were inhibited by the BLT1 specific antagonist, U75302, and by inhibitors of p42/p44 MAPK phosphorylation (U1026), and PI3 kinase (LY294002). Conclusions These observations are the first to suggest a role for a LTB4 -BLT1 signaling axis in ASM responses that may contribute to the pathogenesis of airway remodeling in asthma.</description><subject>Allergy and Immunology</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Bronchi - immunology</subject><subject>Bronchi - metabolism</subject><subject>Cell cycle</subject><subject>Cell Line</subject><subject>Cell Movement</subject><subject>Cell Proliferation</subject><subject>Chronic obstructive pulmonary disease, asthma</subject><subject>Cyclin-Dependent Kinases - metabolism</subject><subject>Dehydrogenases</subject><subject>Epidermal growth factor</subject><subject>Flow cytometry</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Fundamental immunology</subject><subject>Gene Expression Regulation</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Immunopathology</subject><subject>Kinases</subject><subject>Medical sciences</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Muscular system</subject><subject>Myocytes, Smooth Muscle - immunology</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Phosphorylation</subject><subject>Pneumology</subject><subject>Polyclonal antibodies</subject><subject>Proteins</subject><subject>Receptors, Leukotriene B4 - genetics</subject><subject>Receptors, Leukotriene B4 - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - metabolism</subject><subject>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</subject><subject>Signal Transduction</subject><subject>Smooth muscle</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkk1v1DAQhi0EokvhD3BAlhDcEsYfm9gXJKjKh1SJA_Rsuc6Y9TaJFzsp7L_HoVELnPwxz7yamXcIec6gZsCaN_t6b12oOYCuQdTA5QOyYaDbqlF8-5BsSoBVTSv1CXmS8x7KWyj9mJwwLdvyzTfk8vzXIWHOIY40eurn0U3lbnva43wdpxRwRPpe0oQOD1NMmRZyNw92pDakn_ZI8xDjtKPDnF2P1GHf56fkkbd9xmfreUouP5x_O_tUXXz5-Pns3UXlpJayso1Q1jHnWdOiEFdtY1GwtukYdA0D7zrWaSW9Vc5zZVH6TkimFG41b1RnxSl5e6t7mK8G7ByOU7K9OaQw2HQ00Qbzb2QMO_M93hgpgLWCF4HXq0CKP2bMkxlCXlqwI8Y5mzI8ASBUAV_-B-7jnMqcsmFbkIptWbvI8VvKpZhzQn9XCgOzeGb2ZvHMLJ4ZEKZ4VpJe_N3EfcpqUgFerYDNzvY-2dGFfMdx1mgNf7h1GlhGfhMwGdeHMZSUazxivi_YZG7AfF3WY9kO0ABSt634DeW4tsw</recordid><startdate>200907</startdate><enddate>200907</enddate><creator>Watanabe, Satoko, BS</creator><creator>Yamasaki, Akira, MD, PhD</creator><creator>Hashimoto, Kiyoshi, MD, PhD</creator><creator>Shigeoka, Yasushi, MD, PhD</creator><creator>Chikumi, Hiroki, MD, PhD</creator><creator>Hasegawa, Yasuyuki, MD, PhD</creator><creator>Sumikawa, Takashi, MD, PhD</creator><creator>Takata, Miyako, PhD</creator><creator>Okazaki, Ryota, MD</creator><creator>Watanabe, Masanari, MD, PhD</creator><creator>Yokogawa, Tsuyoshi, BS</creator><creator>Yamamura, Miki, MD</creator><creator>Hayabuchi, Tatsuya, MD</creator><creator>Gerthoffer, William T., PhD</creator><creator>Halayko, Andrew J., PhD</creator><creator>Shimizu, Eiji, MD, PhD</creator><general>Elsevier</general><general>Elsevier Limited</general><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>200907</creationdate><title>Expression of functional leukotriene B4 receptors on human airway smooth muscle cells</title><author>Watanabe, Satoko, BS ; Yamasaki, Akira, MD, PhD ; Hashimoto, Kiyoshi, MD, PhD ; Shigeoka, Yasushi, MD, PhD ; Chikumi, Hiroki, MD, PhD ; Hasegawa, Yasuyuki, MD, PhD ; Sumikawa, Takashi, MD, PhD ; Takata, Miyako, PhD ; Okazaki, Ryota, MD ; Watanabe, Masanari, MD, PhD ; Yokogawa, Tsuyoshi, BS ; Yamamura, Miki, MD ; Hayabuchi, Tatsuya, MD ; Gerthoffer, William T., PhD ; Halayko, Andrew J., PhD ; Shimizu, Eiji, MD, PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4944-a638ac1cf167e33b76ae3176d10d610fcd1d984fa8cf28ae4fd34188e59268da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Allergy and Immunology</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Bronchi - immunology</topic><topic>Bronchi - metabolism</topic><topic>Cell cycle</topic><topic>Cell Line</topic><topic>Cell Movement</topic><topic>Cell Proliferation</topic><topic>Chronic obstructive pulmonary disease, asthma</topic><topic>Cyclin-Dependent Kinases - metabolism</topic><topic>Dehydrogenases</topic><topic>Epidermal growth factor</topic><topic>Flow cytometry</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Fundamental immunology</topic><topic>Gene Expression Regulation</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Immunopathology</topic><topic>Kinases</topic><topic>Medical sciences</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Muscular system</topic><topic>Myocytes, Smooth Muscle - immunology</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Phosphorylation</topic><topic>Pneumology</topic><topic>Polyclonal antibodies</topic><topic>Proteins</topic><topic>Receptors, Leukotriene B4 - genetics</topic><topic>Receptors, Leukotriene B4 - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - metabolism</topic><topic>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</topic><topic>Signal Transduction</topic><topic>Smooth muscle</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Watanabe, Satoko, BS</creatorcontrib><creatorcontrib>Yamasaki, Akira, MD, PhD</creatorcontrib><creatorcontrib>Hashimoto, Kiyoshi, MD, PhD</creatorcontrib><creatorcontrib>Shigeoka, Yasushi, MD, PhD</creatorcontrib><creatorcontrib>Chikumi, Hiroki, MD, PhD</creatorcontrib><creatorcontrib>Hasegawa, Yasuyuki, MD, PhD</creatorcontrib><creatorcontrib>Sumikawa, Takashi, MD, PhD</creatorcontrib><creatorcontrib>Takata, Miyako, PhD</creatorcontrib><creatorcontrib>Okazaki, Ryota, MD</creatorcontrib><creatorcontrib>Watanabe, Masanari, MD, PhD</creatorcontrib><creatorcontrib>Yokogawa, Tsuyoshi, BS</creatorcontrib><creatorcontrib>Yamamura, Miki, MD</creatorcontrib><creatorcontrib>Hayabuchi, Tatsuya, MD</creatorcontrib><creatorcontrib>Gerthoffer, William T., PhD</creatorcontrib><creatorcontrib>Halayko, Andrew J., PhD</creatorcontrib><creatorcontrib>Shimizu, Eiji, MD, PhD</creatorcontrib><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>Watanabe, Satoko, BS</au><au>Yamasaki, Akira, MD, PhD</au><au>Hashimoto, Kiyoshi, MD, PhD</au><au>Shigeoka, Yasushi, MD, PhD</au><au>Chikumi, Hiroki, MD, PhD</au><au>Hasegawa, Yasuyuki, MD, PhD</au><au>Sumikawa, Takashi, MD, PhD</au><au>Takata, Miyako, PhD</au><au>Okazaki, Ryota, MD</au><au>Watanabe, Masanari, MD, PhD</au><au>Yokogawa, Tsuyoshi, BS</au><au>Yamamura, Miki, MD</au><au>Hayabuchi, Tatsuya, MD</au><au>Gerthoffer, William T., PhD</au><au>Halayko, Andrew J., PhD</au><au>Shimizu, Eiji, MD, PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expression of functional leukotriene B4 receptors on human airway smooth muscle cells</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2009-07</date><risdate>2009</risdate><volume>124</volume><issue>1</issue><spage>59</spage><epage>65.e3</epage><pages>59-65.e3</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><coden>JACIBY</coden><abstract>Background Leukotriene B4 (LTB4 ) increases in induced sputum and exhaled breath condensate in people with asthma. Furthermore, the TH 2-type immune response and airway hyperresponsiveness induced by ovalbumin sensitization is markedly suppressed in LTB4 receptor (BLT) 1 null mice. These studies suggest that LTB4 may contribute to asthma pathophysiology. However, the direct effects of LTB4 on human airway smooth muscle (ASM) have not been studied. Objectives We sought to determine the expression of LTB4 receptors on human ASM and its functional role in mediating responses of human ASM cells, and the effect of LTB4 on these cells. Methods Immunohistochemistry, RT-PCR, Western blotting, and flow cytometry were used to determine the expression of LTB4 receptors. To determine the effect of LTB4 on human ASM cells, cell proliferation was assessed by counting cells, and chemokinesis was assessed by gold particle phagokinesis assay. Results We confirmed expression of both BLT1 and BLT2 in human ASM cells in bronchial tissue and in cell culture. LTB4 markedly induced cyclin D1 expression, proliferation, and chemokinesis of human ASM cells. LTB4 also induced phosphorylation of both p42/p44 mitogen-activated protein kinase (MAPK) and downstream PI3 kinase effector, Akt1. However, we observed no induction of c-Jun N-terminal kinase or p38 MAPK. Notably, LTB4 -induced migration and proliferation of ASM cells were inhibited by the BLT1 specific antagonist, U75302, and by inhibitors of p42/p44 MAPK phosphorylation (U1026), and PI3 kinase (LY294002). Conclusions These observations are the first to suggest a role for a LTB4 -BLT1 signaling axis in ASM responses that may contribute to the pathogenesis of airway remodeling in asthma.</abstract><cop>New York, NY</cop><pub>Elsevier</pub><pmid>19477492</pmid><doi>10.1016/j.jaci.2009.03.024</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals; EZB-FREE-00999 freely available EZB journals |
| subjects | Allergy and Immunology Biological and medical sciences Blotting, Western Bronchi - immunology Bronchi - metabolism Cell cycle Cell Line Cell Movement Cell Proliferation Chronic obstructive pulmonary disease, asthma Cyclin-Dependent Kinases - metabolism Dehydrogenases Epidermal growth factor Flow cytometry Fundamental and applied biological sciences. Psychology Fundamental immunology Gene Expression Regulation Humans Immunohistochemistry Immunopathology Kinases Medical sciences Mitogen-Activated Protein Kinase 3 - metabolism Muscular system Myocytes, Smooth Muscle - immunology Myocytes, Smooth Muscle - metabolism Phosphorylation Pneumology Polyclonal antibodies Proteins Receptors, Leukotriene B4 - genetics Receptors, Leukotriene B4 - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - metabolism Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis Signal Transduction Smooth muscle |
| title | Expression of functional leukotriene B4 receptors on human airway smooth muscle cells |
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