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Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-α-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2
Bone morphogenetic proteins 9 and 10 (BMP9/BMP10) are circulating cytokines with important roles in endothelial homeostasis. The aim of this study was to investigate the roles of BMP9 and BMP10 in mediating monocyte–endothelial interactions using an in vitro flow adhesion assay. Herein, we report th...
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| Published in: | The Journal of biological chemistry 2017-08, Vol.292 (33), p.13714-13726 |
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| creator | Mitrofan, Claudia-Gabriela Appleby, Sarah L. Nash, Gerard B. Mallat, Ziad Chilvers, Edwin R. Upton, Paul D. Morrell, Nicholas W. |
| description | Bone morphogenetic proteins 9 and 10 (BMP9/BMP10) are circulating cytokines with important roles in endothelial homeostasis. The aim of this study was to investigate the roles of BMP9 and BMP10 in mediating monocyte–endothelial interactions using an in vitro flow adhesion assay. Herein, we report that whereas BMP9/BMP10 alone had no effect on monocyte recruitment, at higher concentrations both cytokines synergized with tumor necrosis factor-α (TNFα) to increase recruitment to the vascular endothelium. The BMP9/BMP10-mediated increase in monocyte recruitment in the presence of TNFα was associated with up-regulated expression levels of E-selectin, vascular cell adhesion molecule (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Using siRNAs to type I and II BMP receptors and the signaling intermediaries (Smads), we demonstrated a key role for ALK2 in the BMP9/BMP10-induced surface expression of E-selectin, and both ALK1 and ALK2 in the up-regulation of VCAM-1 and ICAM-1. The type II receptors, BMPR-II and ACTR-IIA were both required for this response, as was Smad1/5. The up-regulation of cell surface adhesion molecules by BMP9/10 in the presence of TNFα was inhibited by LDN193189, which inhibits ALK2 but not ALK1. Furthermore, LDN193189 inhibited monocyte recruitment induced by TNFα and BMP9/10. BMP9/10 increased basal IκBα protein expression, but did not alter p65/RelA levels. Our findings suggest that higher concentrations of BMP9/BMP10 synergize with TNFα to induce the up-regulation of endothelial selectins and adhesion molecules, ultimately resulting in increased monocyte recruitment to the vascular endothelium. This process is mediated mainly via the ALK2 type I receptor, BMPR-II/ACTR-IIA type II receptors, and downstream Smad1/5 signaling. |
| doi_str_mv | 10.1074/jbc.M117.778506 |
| format | article |
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The aim of this study was to investigate the roles of BMP9 and BMP10 in mediating monocyte–endothelial interactions using an in vitro flow adhesion assay. Herein, we report that whereas BMP9/BMP10 alone had no effect on monocyte recruitment, at higher concentrations both cytokines synergized with tumor necrosis factor-α (TNFα) to increase recruitment to the vascular endothelium. The BMP9/BMP10-mediated increase in monocyte recruitment in the presence of TNFα was associated with up-regulated expression levels of E-selectin, vascular cell adhesion molecule (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Using siRNAs to type I and II BMP receptors and the signaling intermediaries (Smads), we demonstrated a key role for ALK2 in the BMP9/BMP10-induced surface expression of E-selectin, and both ALK1 and ALK2 in the up-regulation of VCAM-1 and ICAM-1. The type II receptors, BMPR-II and ACTR-IIA were both required for this response, as was Smad1/5. The up-regulation of cell surface adhesion molecules by BMP9/10 in the presence of TNFα was inhibited by LDN193189, which inhibits ALK2 but not ALK1. Furthermore, LDN193189 inhibited monocyte recruitment induced by TNFα and BMP9/10. BMP9/10 increased basal IκBα protein expression, but did not alter p65/RelA levels. Our findings suggest that higher concentrations of BMP9/BMP10 synergize with TNFα to induce the up-regulation of endothelial selectins and adhesion molecules, ultimately resulting in increased monocyte recruitment to the vascular endothelium. This process is mediated mainly via the ALK2 type I receptor, BMPR-II/ACTR-IIA type II receptors, and downstream Smad1/5 signaling.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M117.778506</identifier><identifier>PMID: 28646109</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Activin Receptors, Type I - antagonists & inhibitors ; Activin Receptors, Type I - genetics ; Activin Receptors, Type I - metabolism ; Activin Receptors, Type II - antagonists & inhibitors ; Activin Receptors, Type II - genetics ; Activin Receptors, Type II - metabolism ; Aorta ; atherosclerosis ; bone morphogenetic protein (BMP) ; Bone Morphogenetic Proteins - metabolism ; Cell Adhesion - drug effects ; Cell Biology ; Cells, Cultured ; E-Selectin - chemistry ; E-Selectin - genetics ; E-Selectin - metabolism ; endothelial cell ; Endothelium, Vascular - cytology ; Endothelium, Vascular - drug effects ; Endothelium, Vascular - immunology ; Endothelium, Vascular - metabolism ; Growth Differentiation Factor 2 ; Growth Differentiation Factors - metabolism ; Humans ; Intercellular Adhesion Molecule-1 - chemistry ; Intercellular Adhesion Molecule-1 - genetics ; Intercellular Adhesion Molecule-1 - metabolism ; Kinetics ; monocyte ; Monocytes - cytology ; Monocytes - drug effects ; Monocytes - immunology ; Monocytes - metabolism ; Phosphorylation - drug effects ; Protein Kinase Inhibitors - pharmacology ; Protein Processing, Post-Translational - drug effects ; Pyrazoles - pharmacology ; Pyrimidines - pharmacology ; RNA Interference ; Signal Transduction - drug effects ; SMAD transcription factor ; Tumor Necrosis Factor-alpha - agonists ; Tumor Necrosis Factor-alpha - metabolism ; Up-Regulation - drug effects ; Vascular Cell Adhesion Molecule-1 - chemistry ; Vascular Cell Adhesion Molecule-1 - genetics ; Vascular Cell Adhesion Molecule-1 - metabolism</subject><ispartof>The Journal of biological chemistry, 2017-08, Vol.292 (33), p.13714-13726</ispartof><rights>2017 © 2017 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2017 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><rights>2017 by The American Society for Biochemistry and Molecular Biology, Inc. 2017 The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c419t-e3debad5de10f04281fc953636951a5d78ed1fc52589152bdfcc81be06f87a9a3</citedby><cites>FETCH-LOGICAL-c419t-e3debad5de10f04281fc953636951a5d78ed1fc52589152bdfcc81be06f87a9a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566526/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566526/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28646109$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mitrofan, Claudia-Gabriela</creatorcontrib><creatorcontrib>Appleby, Sarah L.</creatorcontrib><creatorcontrib>Nash, Gerard B.</creatorcontrib><creatorcontrib>Mallat, Ziad</creatorcontrib><creatorcontrib>Chilvers, Edwin R.</creatorcontrib><creatorcontrib>Upton, Paul D.</creatorcontrib><creatorcontrib>Morrell, Nicholas W.</creatorcontrib><title>Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-α-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Bone morphogenetic proteins 9 and 10 (BMP9/BMP10) are circulating cytokines with important roles in endothelial homeostasis. The aim of this study was to investigate the roles of BMP9 and BMP10 in mediating monocyte–endothelial interactions using an in vitro flow adhesion assay. Herein, we report that whereas BMP9/BMP10 alone had no effect on monocyte recruitment, at higher concentrations both cytokines synergized with tumor necrosis factor-α (TNFα) to increase recruitment to the vascular endothelium. The BMP9/BMP10-mediated increase in monocyte recruitment in the presence of TNFα was associated with up-regulated expression levels of E-selectin, vascular cell adhesion molecule (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Using siRNAs to type I and II BMP receptors and the signaling intermediaries (Smads), we demonstrated a key role for ALK2 in the BMP9/BMP10-induced surface expression of E-selectin, and both ALK1 and ALK2 in the up-regulation of VCAM-1 and ICAM-1. The type II receptors, BMPR-II and ACTR-IIA were both required for this response, as was Smad1/5. The up-regulation of cell surface adhesion molecules by BMP9/10 in the presence of TNFα was inhibited by LDN193189, which inhibits ALK2 but not ALK1. Furthermore, LDN193189 inhibited monocyte recruitment induced by TNFα and BMP9/10. BMP9/10 increased basal IκBα protein expression, but did not alter p65/RelA levels. Our findings suggest that higher concentrations of BMP9/BMP10 synergize with TNFα to induce the up-regulation of endothelial selectins and adhesion molecules, ultimately resulting in increased monocyte recruitment to the vascular endothelium. This process is mediated mainly via the ALK2 type I receptor, BMPR-II/ACTR-IIA type II receptors, and downstream Smad1/5 signaling.</description><subject>Activin Receptors, Type I - antagonists & inhibitors</subject><subject>Activin Receptors, Type I - genetics</subject><subject>Activin Receptors, Type I - metabolism</subject><subject>Activin Receptors, Type II - antagonists & inhibitors</subject><subject>Activin Receptors, Type II - genetics</subject><subject>Activin Receptors, Type II - metabolism</subject><subject>Aorta</subject><subject>atherosclerosis</subject><subject>bone morphogenetic protein (BMP)</subject><subject>Bone Morphogenetic Proteins - metabolism</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Biology</subject><subject>Cells, Cultured</subject><subject>E-Selectin - chemistry</subject><subject>E-Selectin - genetics</subject><subject>E-Selectin - metabolism</subject><subject>endothelial cell</subject><subject>Endothelium, Vascular - cytology</subject><subject>Endothelium, Vascular - drug effects</subject><subject>Endothelium, Vascular - immunology</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Growth Differentiation Factor 2</subject><subject>Growth Differentiation Factors - metabolism</subject><subject>Humans</subject><subject>Intercellular Adhesion Molecule-1 - chemistry</subject><subject>Intercellular Adhesion Molecule-1 - genetics</subject><subject>Intercellular Adhesion Molecule-1 - metabolism</subject><subject>Kinetics</subject><subject>monocyte</subject><subject>Monocytes - cytology</subject><subject>Monocytes - drug effects</subject><subject>Monocytes - immunology</subject><subject>Monocytes - metabolism</subject><subject>Phosphorylation - drug effects</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Processing, Post-Translational - drug effects</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrimidines - pharmacology</subject><subject>RNA Interference</subject><subject>Signal Transduction - drug effects</subject><subject>SMAD transcription factor</subject><subject>Tumor Necrosis Factor-alpha - agonists</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Up-Regulation - drug effects</subject><subject>Vascular Cell Adhesion Molecule-1 - chemistry</subject><subject>Vascular Cell Adhesion Molecule-1 - genetics</subject><subject>Vascular Cell Adhesion Molecule-1 - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp1kcFu1DAQhi0EotvCmRvyEQ7Z2knsxBckWkFBagUHkLhZjj3puk3syHEi7WP1RXgmZrVQwQFfbI3__xvN_IS84mzLWVOf33V2e8N5s22aVjD5hGw4a6uiEvzHU7JhrOSFKkV7Qk7n-Y7hqRV_Tk7KVtaSM7UhDxcxAB1jmnbxFgJkb-mUYgYfqKJvLm6-qrfUBEfxxRmFsDPBAs0LWmgAm-LsZ9obm2Mqfj4UPrjFgkNiiHafgSbULD6PEDLNkeYd0NXMdhlMQpqLWBj8MtLR-DDs6eoNRZhfsT9aYTpwB38P9N4HMwMtX5BnvRlmePn7PiPfP374dvmpuP5y9fny_XVha65yAZWDzjjhgLOe1WXLe6tEJSupBDfCNS04LAncjuKi7Fxvbcs7YLJvG6NMdUbeHbnT0o3gLA6QzKCn5EeT9joar__9CX6nb-OqhZBSlBIB50fAYUlzgv7Ry5k-pKcxPX1ITx_TQ8frv1s-6v_EhQJ1FAAOvnpIerYeMBDncVlZu-j_C_8FgK2vVA</recordid><startdate>20170818</startdate><enddate>20170818</enddate><creator>Mitrofan, Claudia-Gabriela</creator><creator>Appleby, Sarah L.</creator><creator>Nash, Gerard B.</creator><creator>Mallat, Ziad</creator><creator>Chilvers, Edwin R.</creator><creator>Upton, Paul D.</creator><creator>Morrell, Nicholas W.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</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>5PM</scope></search><sort><creationdate>20170818</creationdate><title>Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-α-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2</title><author>Mitrofan, Claudia-Gabriela ; Appleby, Sarah L. ; Nash, Gerard B. ; Mallat, Ziad ; Chilvers, Edwin R. ; Upton, Paul D. ; Morrell, Nicholas W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c419t-e3debad5de10f04281fc953636951a5d78ed1fc52589152bdfcc81be06f87a9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Activin Receptors, Type I - antagonists & inhibitors</topic><topic>Activin Receptors, Type I - genetics</topic><topic>Activin Receptors, Type I - metabolism</topic><topic>Activin Receptors, Type II - antagonists & inhibitors</topic><topic>Activin Receptors, Type II - genetics</topic><topic>Activin Receptors, Type II - metabolism</topic><topic>Aorta</topic><topic>atherosclerosis</topic><topic>bone morphogenetic protein (BMP)</topic><topic>Bone Morphogenetic Proteins - metabolism</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Biology</topic><topic>Cells, Cultured</topic><topic>E-Selectin - chemistry</topic><topic>E-Selectin - genetics</topic><topic>E-Selectin - metabolism</topic><topic>endothelial cell</topic><topic>Endothelium, Vascular - cytology</topic><topic>Endothelium, Vascular - drug effects</topic><topic>Endothelium, Vascular - immunology</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Growth Differentiation Factor 2</topic><topic>Growth Differentiation Factors - metabolism</topic><topic>Humans</topic><topic>Intercellular Adhesion Molecule-1 - chemistry</topic><topic>Intercellular Adhesion Molecule-1 - genetics</topic><topic>Intercellular Adhesion Molecule-1 - metabolism</topic><topic>Kinetics</topic><topic>monocyte</topic><topic>Monocytes - cytology</topic><topic>Monocytes - drug effects</topic><topic>Monocytes - immunology</topic><topic>Monocytes - metabolism</topic><topic>Phosphorylation - drug effects</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Processing, Post-Translational - drug effects</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrimidines - pharmacology</topic><topic>RNA Interference</topic><topic>Signal Transduction - drug effects</topic><topic>SMAD transcription factor</topic><topic>Tumor Necrosis Factor-alpha - agonists</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Up-Regulation - drug effects</topic><topic>Vascular Cell Adhesion Molecule-1 - chemistry</topic><topic>Vascular Cell Adhesion Molecule-1 - genetics</topic><topic>Vascular Cell Adhesion Molecule-1 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mitrofan, Claudia-Gabriela</creatorcontrib><creatorcontrib>Appleby, Sarah L.</creatorcontrib><creatorcontrib>Nash, Gerard B.</creatorcontrib><creatorcontrib>Mallat, Ziad</creatorcontrib><creatorcontrib>Chilvers, Edwin R.</creatorcontrib><creatorcontrib>Upton, Paul D.</creatorcontrib><creatorcontrib>Morrell, Nicholas W.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mitrofan, Claudia-Gabriela</au><au>Appleby, Sarah L.</au><au>Nash, Gerard B.</au><au>Mallat, Ziad</au><au>Chilvers, Edwin R.</au><au>Upton, Paul D.</au><au>Morrell, Nicholas W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-α-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2017-08-18</date><risdate>2017</risdate><volume>292</volume><issue>33</issue><spage>13714</spage><epage>13726</epage><pages>13714-13726</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><notes>Both authors should be considered as senior authors.</notes><notes>Both authors contributed equally to the results of this work.</notes><notes>Edited by Xiao-Fan Wang</notes><abstract>Bone morphogenetic proteins 9 and 10 (BMP9/BMP10) are circulating cytokines with important roles in endothelial homeostasis. The aim of this study was to investigate the roles of BMP9 and BMP10 in mediating monocyte–endothelial interactions using an in vitro flow adhesion assay. Herein, we report that whereas BMP9/BMP10 alone had no effect on monocyte recruitment, at higher concentrations both cytokines synergized with tumor necrosis factor-α (TNFα) to increase recruitment to the vascular endothelium. The BMP9/BMP10-mediated increase in monocyte recruitment in the presence of TNFα was associated with up-regulated expression levels of E-selectin, vascular cell adhesion molecule (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Using siRNAs to type I and II BMP receptors and the signaling intermediaries (Smads), we demonstrated a key role for ALK2 in the BMP9/BMP10-induced surface expression of E-selectin, and both ALK1 and ALK2 in the up-regulation of VCAM-1 and ICAM-1. The type II receptors, BMPR-II and ACTR-IIA were both required for this response, as was Smad1/5. The up-regulation of cell surface adhesion molecules by BMP9/10 in the presence of TNFα was inhibited by LDN193189, which inhibits ALK2 but not ALK1. Furthermore, LDN193189 inhibited monocyte recruitment induced by TNFα and BMP9/10. BMP9/10 increased basal IκBα protein expression, but did not alter p65/RelA levels. Our findings suggest that higher concentrations of BMP9/BMP10 synergize with TNFα to induce the up-regulation of endothelial selectins and adhesion molecules, ultimately resulting in increased monocyte recruitment to the vascular endothelium. This process is mediated mainly via the ALK2 type I receptor, BMPR-II/ACTR-IIA type II receptors, and downstream Smad1/5 signaling.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28646109</pmid><doi>10.1074/jbc.M117.778506</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2017-08, Vol.292 (33), p.13714-13726 |
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| subjects | Activin Receptors, Type I - antagonists & inhibitors Activin Receptors, Type I - genetics Activin Receptors, Type I - metabolism Activin Receptors, Type II - antagonists & inhibitors Activin Receptors, Type II - genetics Activin Receptors, Type II - metabolism Aorta atherosclerosis bone morphogenetic protein (BMP) Bone Morphogenetic Proteins - metabolism Cell Adhesion - drug effects Cell Biology Cells, Cultured E-Selectin - chemistry E-Selectin - genetics E-Selectin - metabolism endothelial cell Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Endothelium, Vascular - immunology Endothelium, Vascular - metabolism Growth Differentiation Factor 2 Growth Differentiation Factors - metabolism Humans Intercellular Adhesion Molecule-1 - chemistry Intercellular Adhesion Molecule-1 - genetics Intercellular Adhesion Molecule-1 - metabolism Kinetics monocyte Monocytes - cytology Monocytes - drug effects Monocytes - immunology Monocytes - metabolism Phosphorylation - drug effects Protein Kinase Inhibitors - pharmacology Protein Processing, Post-Translational - drug effects Pyrazoles - pharmacology Pyrimidines - pharmacology RNA Interference Signal Transduction - drug effects SMAD transcription factor Tumor Necrosis Factor-alpha - agonists Tumor Necrosis Factor-alpha - metabolism Up-Regulation - drug effects Vascular Cell Adhesion Molecule-1 - chemistry Vascular Cell Adhesion Molecule-1 - genetics Vascular Cell Adhesion Molecule-1 - metabolism |
| title | Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-α-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2 |
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