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Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells
Objectives: To test whether the active metabolite of leflunomide (LEF-M), in addition to blocking the proliferation of activated lymphocytes by inhibiting dihydro-orotate dehydrogenase (DHODH), influences the transendothelial migration (TEM) of peripheral blood mononuclear cells (PBMC). Methods: In...
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| Published in: | Annals of the rheumatic diseases 2004-12, Vol.63 (12), p.1632-1637 |
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| container_end_page | 1637 |
| container_issue | 12 |
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| container_title | Annals of the rheumatic diseases |
| container_volume | 63 |
| creator | Grisar, J Aringer, M Köller, M D Stummvoll, G H Eselböck, D Zwölfer, B Steiner, C W Zierhut, B Wagner, L Pietschmann, P Smolen, J S |
| description | Objectives: To test whether the active metabolite of leflunomide (LEF-M), in addition to blocking the proliferation of activated lymphocytes by inhibiting dihydro-orotate dehydrogenase (DHODH), influences the transendothelial migration (TEM) of peripheral blood mononuclear cells (PBMC). Methods: In an in vitro model of PBMC transmigration through an endothelial cell (EC) barrier, PBMC were re-collected in three groups: cells not adherent to the EC, cells bound to, and cells which had migrated through, the EC layer. Experiments in which cells were pretreated with LEF-M (in the absence or in the presence of uridine) were compared with parallel experiments in the presence of medium alone. Results: Preincubation of EC with LEF-M led to a 36 (SEM 16)% reduction in PBMC TEM (p |
| doi_str_mv | 10.1136/ard.2003.018440 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1754829</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>67088728</sourcerecordid><originalsourceid>FETCH-LOGICAL-b520t-95657f14955cbe9292c8d44ffc0eab93ba9b9ea69eb4ec1a9b17624372e92ec73</originalsourceid><addsrcrecordid>eNqFkcFrFDEYxQdR7Fo9e5MBsQdhtkkmmSSXgiy1KosiWPEWksw33ayZZE1mRP97s-7SqhdP4cv3y-O9vKp6itES47Y716lfEoTaJcKCUnSvWmDaiYagDt2vFqhsGio7flI9ynlbRiSweFidYMYoR0Isqus1DH4OcXQ91C5snHFTrqekQ4bQx2kD3mlfj-4m6cnFUMeh3kFyuw2kcm98jH09xhDDbD3oVFvwPj-uHgzaZ3hyPE-r69eXn1ZvmvWHq7erV-vGMIKmRrKO8QFTyZg1IIkkVvSUDoNFoI1sjZZGgu4kGAoWlwnzjtCWkwKD5e1pdXHQ3c1mhN5CKM692iU36vRTRe3U35vgNuomfleYMyqILAJnR4EUv82QJzW6vI-gA8Q5q27_S5yIAj7_B9zGOYUSrmhxLgVmFBfq_EDZFHNOMNxawUjtC1OlMLUvTB0KKy-e_Zngjj82VIAXR0Bnq_1QmrEu33FdSyj9zTUHzuUJftzudfpaQrScqfefV-rjGn9h_B1VV4V_eeDNuP2vy18Z_Lym</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1777981541</pqid></control><display><type>article</type><title>Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells</title><source>PubMed Central (Open access)</source><creator>Grisar, J ; Aringer, M ; Köller, M D ; Stummvoll, G H ; Eselböck, D ; Zwölfer, B ; Steiner, C W ; Zierhut, B ; Wagner, L ; Pietschmann, P ; Smolen, J S</creator><creatorcontrib>Grisar, J ; Aringer, M ; Köller, M D ; Stummvoll, G H ; Eselböck, D ; Zwölfer, B ; Steiner, C W ; Zierhut, B ; Wagner, L ; Pietschmann, P ; Smolen, J S</creatorcontrib><description>Objectives: To test whether the active metabolite of leflunomide (LEF-M), in addition to blocking the proliferation of activated lymphocytes by inhibiting dihydro-orotate dehydrogenase (DHODH), influences the transendothelial migration (TEM) of peripheral blood mononuclear cells (PBMC). Methods: In an in vitro model of PBMC transmigration through an endothelial cell (EC) barrier, PBMC were re-collected in three groups: cells not adherent to the EC, cells bound to, and cells which had migrated through, the EC layer. Experiments in which cells were pretreated with LEF-M (in the absence or in the presence of uridine) were compared with parallel experiments in the presence of medium alone. Results: Preincubation of EC with LEF-M led to a 36 (SEM 16)% reduction in PBMC TEM (p<0.05). Likewise, preincubation of PBMC induced a reduction in their TEM of 39 (9)% (p<0.005). Incubation of both PBMC and EC with LEF-M had an additive effect (mean reduction of 48 (6)%, p<0.005). Incubation of PBMC with LEF-M also decreased monocytic CD44 expression (p<0.005) and PBMC-hyaluronan binding (p<0.05). Incubation of cells with LEF-M and uridine in addition to LEF-M reversed the inhibition of migration, suggesting that the observed effects were due to DHODH inhibition. Fluorocytometric analysis of PBMC subsets within the migrated population showed a decrease of monocytes, but not of B or T cells, after LEF-M treatment. Conclusions: LEF-M reduces monocytic adhesion molecule expression and TEM and may thus interfere with monocyte and EC activities in RA. Thus, the clinical effects of leflunomide may, at least in part, be due to blocking cell traffic into the inflamed synovia.</description><identifier>ISSN: 0003-4967</identifier><identifier>EISSN: 1468-2060</identifier><identifier>DOI: 10.1136/ard.2003.018440</identifier><identifier>PMID: 15547088</identifier><identifier>CODEN: ARDIAO</identifier><language>eng</language><publisher>London: BMJ Publishing Group Ltd and European League Against Rheumatism</publisher><subject>A77 1726 ; A771 726 ; Antirheumatic Agents - antagonists & inhibitors ; Antirheumatic Agents - pharmacology ; Biological and medical sciences ; Biopsy ; BND ; Bones, joints and connective tissue. Antiinflammatory agents ; bound ; Cell adhesion & migration ; Cell Adhesion - drug effects ; Cell division ; Cell Movement - drug effects ; Cells, Cultured ; Chemotaxis, Leukocyte - drug effects ; Collagen ; Cytokines ; Dex ; dexamethasone ; DHODH ; dihydro-orotate dehydrogenase ; disease modifying antirheumatic drug ; DMARD ; endothelial cell(s) ; endothelium ; Endothelium, Vascular - cytology ; Endothelium, Vascular - drug effects ; Enzymes ; Evacuations & rescues ; Experiments ; Extended Report ; Flow Cytometry ; Humans ; Hyaluronic Acid - metabolism ; Isoxazoles - antagonists & inhibitors ; Isoxazoles - pharmacology ; LEF-M ; leflunomide ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - physiology ; Lymphocytes ; macrophage inhibitory protein-1α ; MCP ; mean fluorescence intensity ; Medical sciences ; metabolite of leflunomide ; methotrexate ; Methotrexate - pharmacology ; MFI ; MIG ; migrated ; MIP-1α ; monocyte chemotactic protein ; MTX ; NAD ; NF-κB ; non-adherent ; nuclear factor κB ; PBMC ; PBS ; peripheral blood mononuclear cell(s) ; peripheral blood mononuclear cells ; Pharmacology. Drug treatments ; phosphate buffered saline ; rheumatoid arthritis ; TEM ; Transcription factors ; transendothelial migration ; Uridine - pharmacology</subject><ispartof>Annals of the rheumatic diseases, 2004-12, Vol.63 (12), p.1632-1637</ispartof><rights>Copyright 2004 by Annals of the Rheumatic Diseases</rights><rights>2005 INIST-CNRS</rights><rights>Copyright: 2004 Copyright 2004 by Annals of the Rheumatic Diseases</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b520t-95657f14955cbe9292c8d44ffc0eab93ba9b9ea69eb4ec1a9b17624372e92ec73</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1754829/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1754829/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16324488$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15547088$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grisar, J</creatorcontrib><creatorcontrib>Aringer, M</creatorcontrib><creatorcontrib>Köller, M D</creatorcontrib><creatorcontrib>Stummvoll, G H</creatorcontrib><creatorcontrib>Eselböck, D</creatorcontrib><creatorcontrib>Zwölfer, B</creatorcontrib><creatorcontrib>Steiner, C W</creatorcontrib><creatorcontrib>Zierhut, B</creatorcontrib><creatorcontrib>Wagner, L</creatorcontrib><creatorcontrib>Pietschmann, P</creatorcontrib><creatorcontrib>Smolen, J S</creatorcontrib><title>Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells</title><title>Annals of the rheumatic diseases</title><addtitle>Ann Rheum Dis</addtitle><description>Objectives: To test whether the active metabolite of leflunomide (LEF-M), in addition to blocking the proliferation of activated lymphocytes by inhibiting dihydro-orotate dehydrogenase (DHODH), influences the transendothelial migration (TEM) of peripheral blood mononuclear cells (PBMC). Methods: In an in vitro model of PBMC transmigration through an endothelial cell (EC) barrier, PBMC were re-collected in three groups: cells not adherent to the EC, cells bound to, and cells which had migrated through, the EC layer. Experiments in which cells were pretreated with LEF-M (in the absence or in the presence of uridine) were compared with parallel experiments in the presence of medium alone. Results: Preincubation of EC with LEF-M led to a 36 (SEM 16)% reduction in PBMC TEM (p<0.05). Likewise, preincubation of PBMC induced a reduction in their TEM of 39 (9)% (p<0.005). Incubation of both PBMC and EC with LEF-M had an additive effect (mean reduction of 48 (6)%, p<0.005). Incubation of PBMC with LEF-M also decreased monocytic CD44 expression (p<0.005) and PBMC-hyaluronan binding (p<0.05). Incubation of cells with LEF-M and uridine in addition to LEF-M reversed the inhibition of migration, suggesting that the observed effects were due to DHODH inhibition. Fluorocytometric analysis of PBMC subsets within the migrated population showed a decrease of monocytes, but not of B or T cells, after LEF-M treatment. Conclusions: LEF-M reduces monocytic adhesion molecule expression and TEM and may thus interfere with monocyte and EC activities in RA. Thus, the clinical effects of leflunomide may, at least in part, be due to blocking cell traffic into the inflamed synovia.</description><subject>A77 1726</subject><subject>A771 726</subject><subject>Antirheumatic Agents - antagonists & inhibitors</subject><subject>Antirheumatic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Biopsy</subject><subject>BND</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>bound</subject><subject>Cell adhesion & migration</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell division</subject><subject>Cell Movement - drug effects</subject><subject>Cells, Cultured</subject><subject>Chemotaxis, Leukocyte - drug effects</subject><subject>Collagen</subject><subject>Cytokines</subject><subject>Dex</subject><subject>dexamethasone</subject><subject>DHODH</subject><subject>dihydro-orotate dehydrogenase</subject><subject>disease modifying antirheumatic drug</subject><subject>DMARD</subject><subject>endothelial cell(s)</subject><subject>endothelium</subject><subject>Endothelium, Vascular - cytology</subject><subject>Endothelium, Vascular - drug effects</subject><subject>Enzymes</subject><subject>Evacuations & rescues</subject><subject>Experiments</subject><subject>Extended Report</subject><subject>Flow Cytometry</subject><subject>Humans</subject><subject>Hyaluronic Acid - metabolism</subject><subject>Isoxazoles - antagonists & inhibitors</subject><subject>Isoxazoles - pharmacology</subject><subject>LEF-M</subject><subject>leflunomide</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - physiology</subject><subject>Lymphocytes</subject><subject>macrophage inhibitory protein-1α</subject><subject>MCP</subject><subject>mean fluorescence intensity</subject><subject>Medical sciences</subject><subject>metabolite of leflunomide</subject><subject>methotrexate</subject><subject>Methotrexate - pharmacology</subject><subject>MFI</subject><subject>MIG</subject><subject>migrated</subject><subject>MIP-1α</subject><subject>monocyte chemotactic protein</subject><subject>MTX</subject><subject>NAD</subject><subject>NF-κB</subject><subject>non-adherent</subject><subject>nuclear factor κB</subject><subject>PBMC</subject><subject>PBS</subject><subject>peripheral blood mononuclear cell(s)</subject><subject>peripheral blood mononuclear cells</subject><subject>Pharmacology. Drug treatments</subject><subject>phosphate buffered saline</subject><subject>rheumatoid arthritis</subject><subject>TEM</subject><subject>Transcription factors</subject><subject>transendothelial migration</subject><subject>Uridine - pharmacology</subject><issn>0003-4967</issn><issn>1468-2060</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNqFkcFrFDEYxQdR7Fo9e5MBsQdhtkkmmSSXgiy1KosiWPEWksw33ayZZE1mRP97s-7SqhdP4cv3y-O9vKp6itES47Y716lfEoTaJcKCUnSvWmDaiYagDt2vFqhsGio7flI9ynlbRiSweFidYMYoR0Isqus1DH4OcXQ91C5snHFTrqekQ4bQx2kD3mlfj-4m6cnFUMeh3kFyuw2kcm98jH09xhDDbD3oVFvwPj-uHgzaZ3hyPE-r69eXn1ZvmvWHq7erV-vGMIKmRrKO8QFTyZg1IIkkVvSUDoNFoI1sjZZGgu4kGAoWlwnzjtCWkwKD5e1pdXHQ3c1mhN5CKM692iU36vRTRe3U35vgNuomfleYMyqILAJnR4EUv82QJzW6vI-gA8Q5q27_S5yIAj7_B9zGOYUSrmhxLgVmFBfq_EDZFHNOMNxawUjtC1OlMLUvTB0KKy-e_Zngjj82VIAXR0Bnq_1QmrEu33FdSyj9zTUHzuUJftzudfpaQrScqfefV-rjGn9h_B1VV4V_eeDNuP2vy18Z_Lym</recordid><startdate>20041201</startdate><enddate>20041201</enddate><creator>Grisar, J</creator><creator>Aringer, M</creator><creator>Köller, M D</creator><creator>Stummvoll, G H</creator><creator>Eselböck, D</creator><creator>Zwölfer, B</creator><creator>Steiner, C W</creator><creator>Zierhut, B</creator><creator>Wagner, L</creator><creator>Pietschmann, P</creator><creator>Smolen, J S</creator><general>BMJ Publishing Group Ltd and European League Against Rheumatism</general><general>BMJ</general><general>BMJ Publishing Group LTD</general><scope>BSCLL</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20041201</creationdate><title>Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells</title><author>Grisar, J ; Aringer, M ; Köller, M D ; Stummvoll, G H ; Eselböck, D ; Zwölfer, B ; Steiner, C W ; Zierhut, B ; Wagner, L ; Pietschmann, P ; Smolen, J S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b520t-95657f14955cbe9292c8d44ffc0eab93ba9b9ea69eb4ec1a9b17624372e92ec73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>A77 1726</topic><topic>A771 726</topic><topic>Antirheumatic Agents - antagonists & inhibitors</topic><topic>Antirheumatic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Biopsy</topic><topic>BND</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>bound</topic><topic>Cell adhesion & migration</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell division</topic><topic>Cell Movement - drug effects</topic><topic>Cells, Cultured</topic><topic>Chemotaxis, Leukocyte - drug effects</topic><topic>Collagen</topic><topic>Cytokines</topic><topic>Dex</topic><topic>dexamethasone</topic><topic>DHODH</topic><topic>dihydro-orotate dehydrogenase</topic><topic>disease modifying antirheumatic drug</topic><topic>DMARD</topic><topic>endothelial cell(s)</topic><topic>endothelium</topic><topic>Endothelium, Vascular - cytology</topic><topic>Endothelium, Vascular - drug effects</topic><topic>Enzymes</topic><topic>Evacuations & rescues</topic><topic>Experiments</topic><topic>Extended Report</topic><topic>Flow Cytometry</topic><topic>Humans</topic><topic>Hyaluronic Acid - metabolism</topic><topic>Isoxazoles - antagonists & inhibitors</topic><topic>Isoxazoles - pharmacology</topic><topic>LEF-M</topic><topic>leflunomide</topic><topic>Leukocytes, Mononuclear - drug effects</topic><topic>Leukocytes, Mononuclear - physiology</topic><topic>Lymphocytes</topic><topic>macrophage inhibitory protein-1α</topic><topic>MCP</topic><topic>mean fluorescence intensity</topic><topic>Medical sciences</topic><topic>metabolite of leflunomide</topic><topic>methotrexate</topic><topic>Methotrexate - pharmacology</topic><topic>MFI</topic><topic>MIG</topic><topic>migrated</topic><topic>MIP-1α</topic><topic>monocyte chemotactic protein</topic><topic>MTX</topic><topic>NAD</topic><topic>NF-κB</topic><topic>non-adherent</topic><topic>nuclear factor κB</topic><topic>PBMC</topic><topic>PBS</topic><topic>peripheral blood mononuclear cell(s)</topic><topic>peripheral blood mononuclear cells</topic><topic>Pharmacology. Drug treatments</topic><topic>phosphate buffered saline</topic><topic>rheumatoid arthritis</topic><topic>TEM</topic><topic>Transcription factors</topic><topic>transendothelial migration</topic><topic>Uridine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grisar, J</creatorcontrib><creatorcontrib>Aringer, M</creatorcontrib><creatorcontrib>Köller, M D</creatorcontrib><creatorcontrib>Stummvoll, G H</creatorcontrib><creatorcontrib>Eselböck, D</creatorcontrib><creatorcontrib>Zwölfer, B</creatorcontrib><creatorcontrib>Steiner, C W</creatorcontrib><creatorcontrib>Zierhut, B</creatorcontrib><creatorcontrib>Wagner, L</creatorcontrib><creatorcontrib>Pietschmann, P</creatorcontrib><creatorcontrib>Smolen, J S</creatorcontrib><collection>Istex</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>ProQuest Central (Corporate)</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>ProQuest Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Science Journals</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Annals of the rheumatic diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grisar, J</au><au>Aringer, M</au><au>Köller, M D</au><au>Stummvoll, G H</au><au>Eselböck, D</au><au>Zwölfer, B</au><au>Steiner, C W</au><au>Zierhut, B</au><au>Wagner, L</au><au>Pietschmann, P</au><au>Smolen, J S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells</atitle><jtitle>Annals of the rheumatic diseases</jtitle><addtitle>Ann Rheum Dis</addtitle><date>2004-12-01</date><risdate>2004</risdate><volume>63</volume><issue>12</issue><spage>1632</spage><epage>1637</epage><pages>1632-1637</pages><issn>0003-4967</issn><eissn>1468-2060</eissn><coden>ARDIAO</coden><abstract>Objectives: To test whether the active metabolite of leflunomide (LEF-M), in addition to blocking the proliferation of activated lymphocytes by inhibiting dihydro-orotate dehydrogenase (DHODH), influences the transendothelial migration (TEM) of peripheral blood mononuclear cells (PBMC). Methods: In an in vitro model of PBMC transmigration through an endothelial cell (EC) barrier, PBMC were re-collected in three groups: cells not adherent to the EC, cells bound to, and cells which had migrated through, the EC layer. Experiments in which cells were pretreated with LEF-M (in the absence or in the presence of uridine) were compared with parallel experiments in the presence of medium alone. Results: Preincubation of EC with LEF-M led to a 36 (SEM 16)% reduction in PBMC TEM (p<0.05). Likewise, preincubation of PBMC induced a reduction in their TEM of 39 (9)% (p<0.005). Incubation of both PBMC and EC with LEF-M had an additive effect (mean reduction of 48 (6)%, p<0.005). Incubation of PBMC with LEF-M also decreased monocytic CD44 expression (p<0.005) and PBMC-hyaluronan binding (p<0.05). Incubation of cells with LEF-M and uridine in addition to LEF-M reversed the inhibition of migration, suggesting that the observed effects were due to DHODH inhibition. Fluorocytometric analysis of PBMC subsets within the migrated population showed a decrease of monocytes, but not of B or T cells, after LEF-M treatment. Conclusions: LEF-M reduces monocytic adhesion molecule expression and TEM and may thus interfere with monocyte and EC activities in RA. Thus, the clinical effects of leflunomide may, at least in part, be due to blocking cell traffic into the inflamed synovia.</abstract><cop>London</cop><pub>BMJ Publishing Group Ltd and European League Against Rheumatism</pub><pmid>15547088</pmid><doi>10.1136/ard.2003.018440</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Annals of the rheumatic diseases, 2004-12, Vol.63 (12), p.1632-1637 |
| issn | 0003-4967 1468-2060 |
| language | eng |
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| source | PubMed Central (Open access) |
| subjects | A77 1726 A771 726 Antirheumatic Agents - antagonists & inhibitors Antirheumatic Agents - pharmacology Biological and medical sciences Biopsy BND Bones, joints and connective tissue. Antiinflammatory agents bound Cell adhesion & migration Cell Adhesion - drug effects Cell division Cell Movement - drug effects Cells, Cultured Chemotaxis, Leukocyte - drug effects Collagen Cytokines Dex dexamethasone DHODH dihydro-orotate dehydrogenase disease modifying antirheumatic drug DMARD endothelial cell(s) endothelium Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Enzymes Evacuations & rescues Experiments Extended Report Flow Cytometry Humans Hyaluronic Acid - metabolism Isoxazoles - antagonists & inhibitors Isoxazoles - pharmacology LEF-M leflunomide Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - physiology Lymphocytes macrophage inhibitory protein-1α MCP mean fluorescence intensity Medical sciences metabolite of leflunomide methotrexate Methotrexate - pharmacology MFI MIG migrated MIP-1α monocyte chemotactic protein MTX NAD NF-κB non-adherent nuclear factor κB PBMC PBS peripheral blood mononuclear cell(s) peripheral blood mononuclear cells Pharmacology. Drug treatments phosphate buffered saline rheumatoid arthritis TEM Transcription factors transendothelial migration Uridine - pharmacology |
| title | Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-07T20%3A22%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Leflunomide%20inhibits%20transendothelial%20migration%20of%20peripheral%20blood%20mononuclear%20cells&rft.jtitle=Annals%20of%20the%20rheumatic%20diseases&rft.au=Grisar,%20J&rft.date=2004-12-01&rft.volume=63&rft.issue=12&rft.spage=1632&rft.epage=1637&rft.pages=1632-1637&rft.issn=0003-4967&rft.eissn=1468-2060&rft.coden=ARDIAO&rft_id=info:doi/10.1136/ard.2003.018440&rft_dat=%3Cproquest_pubme%3E67088728%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-b520t-95657f14955cbe9292c8d44ffc0eab93ba9b9ea69eb4ec1a9b17624372e92ec73%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1777981541&rft_id=info:pmid/15547088&rfr_iscdi=true |