Intrarenal cytokine gene expression in lupus nephritis

Background: Lupus nephritis is characterised by intrarenal inflammation and lymphocyte activation. Aim: To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis. Methods: 36 consecutive patients with systemic lupus erythematosus having...

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Veröffentlicht in:Annals of the rheumatic diseases 2007-07, Vol.66 (7), p.886-892
Hauptverfasser: Chan, Rebecca Wing-Yan, Lai, Fernand Mac-Moune, Li, Edmund Kwok-Ming, Tam, Lai-Shan, Chow, Kai-Ming, Lai, Ka-Bik, Li, Philip Kam-Tao, Szeto, Cheuk-Chun
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container_end_page 892
container_issue 7
container_start_page 886
container_title Annals of the rheumatic diseases
container_volume 66
creator Chan, Rebecca Wing-Yan
Lai, Fernand Mac-Moune
Li, Edmund Kwok-Ming
Tam, Lai-Shan
Chow, Kai-Ming
Lai, Ka-Bik
Li, Philip Kam-Tao
Szeto, Cheuk-Chun
description Background: Lupus nephritis is characterised by intrarenal inflammation and lymphocyte activation. Aim: To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis. Methods: 36 consecutive patients with systemic lupus erythematosus having active renal disease were recruited, and they were required to undergo kidney biopsy. Glomerular and tubulointestitial cytokine expression of interleukin (IL)2, 4, 10, 12, 18, interferon γ (IFN)γ, T-bet (the Th1 transcription factor), GATA-3 (the Th2 transcription factor), transforming growth factorβ and monocyte chemoattractant protein (MCP)1 were studied by laser microdissection of the renal biopsy specimen, followed by real-time quantitative PCR. Results: There were 13 patients with World Health Organization class III nephritis, 14 patients with class IV nephritis and 9 patients with class V nephritis. There was a significant correlation between serum C3, C4 and anti-double strand DNA antibody level with glomerular expression of T-bet, IFNγ and IL2. There was a significant correlation between histological activity index and glomerular expression of IL12, IL18, IL10 and MCP1. In addition, the degree of glomerular leucocyte infiltration significantly correlated with glomerular expression of IFNγ, IL10, IL12 and IL18. By contrast, histological chronicity index correlated with the tubulointerstitial expression of IL2, MCP1 and GATA-3. Conclusions: Intraglomerular expression of certain target genes correlate with the severity of systemic as well as histological activity, whereas the tubulointerstitial expression of other target genes correlate with the degree of chronic kidney scarring. This result may shed light on the immunopathogenesis of lupus nephritis.
doi_str_mv 10.1136/ard.2006.063123
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Aim: To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis. Methods: 36 consecutive patients with systemic lupus erythematosus having active renal disease were recruited, and they were required to undergo kidney biopsy. Glomerular and tubulointestitial cytokine expression of interleukin (IL)2, 4, 10, 12, 18, interferon γ (IFN)γ, T-bet (the Th1 transcription factor), GATA-3 (the Th2 transcription factor), transforming growth factorβ and monocyte chemoattractant protein (MCP)1 were studied by laser microdissection of the renal biopsy specimen, followed by real-time quantitative PCR. Results: There were 13 patients with World Health Organization class III nephritis, 14 patients with class IV nephritis and 9 patients with class V nephritis. There was a significant correlation between serum C3, C4 and anti-double strand DNA antibody level with glomerular expression of T-bet, IFNγ and IL2. There was a significant correlation between histological activity index and glomerular expression of IL12, IL18, IL10 and MCP1. In addition, the degree of glomerular leucocyte infiltration significantly correlated with glomerular expression of IFNγ, IL10, IL12 and IL18. By contrast, histological chronicity index correlated with the tubulointerstitial expression of IL2, MCP1 and GATA-3. Conclusions: Intraglomerular expression of certain target genes correlate with the severity of systemic as well as histological activity, whereas the tubulointerstitial expression of other target genes correlate with the degree of chronic kidney scarring. This result may shed light on the immunopathogenesis of lupus nephritis.</description><identifier>ISSN: 0003-4967</identifier><identifier>EISSN: 1468-2060</identifier><identifier>DOI: 10.1136/ard.2006.063123</identifier><identifier>PMID: 17324967</identifier><identifier>CODEN: ARDIAO</identifier><language>eng</language><publisher>London: BMJ Publishing Group Ltd and European League Against Rheumatism</publisher><subject>activity index ; Adult ; Biological and medical sciences ; Chemokine CCL2 - analysis ; Chemokine CCL2 - urine ; chronicity index ; Cytokines ; Cytokines - analysis ; Cytokines - urine ; Deoxyribonucleic acid ; DNA ; double strand ; Extended Report ; Female ; GATA3 Transcription Factor - analysis ; GATA3 Transcription Factor - urine ; Gene expression ; Gene Expression - genetics ; Gene Expression - immunology ; Genetic engineering ; Humans ; IFN ; interferon ; Interferon-gamma - analysis ; Interferon-gamma - urine ; interleukin ; Interleukins - analysis ; Interleukins - urine ; Kidney - immunology ; Kidney - pathology ; Kidney diseases ; Kidney Glomerulus - immunology ; Kidney Glomerulus - pathology ; Kidney Tubules - immunology ; Kidney Tubules - pathology ; Kidneys ; Lasers ; Leukocytes - immunology ; Lupus ; Lupus Nephritis - genetics ; Lupus Nephritis - immunology ; Lupus Nephritis - pathology ; Male ; MCP ; Medical sciences ; messenger RNA ; Methods ; monocyte chemoattractant protein ; mRNA ; Nephrology. Urinary tract diseases ; Polyethylene ; real-time quantitative PCR ; ribosomal RNA ; Rodents ; rRNA ; RT-QPCR ; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis ; SLE ; SLEDAI ; Studies ; systemic lupus erythematosus ; Systemic Lupus Erythematosus Disease Activity Index ; T-Box Domain Proteins - analysis ; T-Box Domain Proteins - urine ; Transcription factors ; Transforming Growth Factor beta - analysis ; Transforming Growth Factor beta - urine ; Urinary system involvement in other diseases. Miscellaneous ; WHO ; World Health Organization</subject><ispartof>Annals of the rheumatic diseases, 2007-07, Vol.66 (7), p.886-892</ispartof><rights>Copyright 2007 by Annals of the Rheumatic Diseases</rights><rights>2007 INIST-CNRS</rights><rights>Copyright: 2007 Copyright 2007 by Annals of the Rheumatic Diseases</rights><rights>Copyright © 2007 BMJ Publishing Group and European League Against Rheumatism</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b553t-2f504b82ae1ee2c0ae538dcb2218c6843410ebfed91071685cf1d735f2a40ad93</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttp://ard.bmj.com/content/66/7/886.full.pdf$$EPDF$$P50$$Gbmj$$H</linktopdf><linktohtml>$$Uhttp://ard.bmj.com/content/66/7/886.full$$EHTML$$P50$$Gbmj$$H</linktohtml><link.rule.ids>114,115,230,315,728,781,785,886,3197,23576,27929,27930,53796,53798,77605,77636</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=18825256$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17324967$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chan, Rebecca Wing-Yan</creatorcontrib><creatorcontrib>Lai, Fernand Mac-Moune</creatorcontrib><creatorcontrib>Li, Edmund Kwok-Ming</creatorcontrib><creatorcontrib>Tam, Lai-Shan</creatorcontrib><creatorcontrib>Chow, Kai-Ming</creatorcontrib><creatorcontrib>Lai, Ka-Bik</creatorcontrib><creatorcontrib>Li, Philip Kam-Tao</creatorcontrib><creatorcontrib>Szeto, Cheuk-Chun</creatorcontrib><title>Intrarenal cytokine gene expression in lupus nephritis</title><title>Annals of the rheumatic diseases</title><addtitle>Ann Rheum Dis</addtitle><description>Background: Lupus nephritis is characterised by intrarenal inflammation and lymphocyte activation. Aim: To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis. Methods: 36 consecutive patients with systemic lupus erythematosus having active renal disease were recruited, and they were required to undergo kidney biopsy. Glomerular and tubulointestitial cytokine expression of interleukin (IL)2, 4, 10, 12, 18, interferon γ (IFN)γ, T-bet (the Th1 transcription factor), GATA-3 (the Th2 transcription factor), transforming growth factorβ and monocyte chemoattractant protein (MCP)1 were studied by laser microdissection of the renal biopsy specimen, followed by real-time quantitative PCR. Results: There were 13 patients with World Health Organization class III nephritis, 14 patients with class IV nephritis and 9 patients with class V nephritis. There was a significant correlation between serum C3, C4 and anti-double strand DNA antibody level with glomerular expression of T-bet, IFNγ and IL2. There was a significant correlation between histological activity index and glomerular expression of IL12, IL18, IL10 and MCP1. In addition, the degree of glomerular leucocyte infiltration significantly correlated with glomerular expression of IFNγ, IL10, IL12 and IL18. By contrast, histological chronicity index correlated with the tubulointerstitial expression of IL2, MCP1 and GATA-3. Conclusions: Intraglomerular expression of certain target genes correlate with the severity of systemic as well as histological activity, whereas the tubulointerstitial expression of other target genes correlate with the degree of chronic kidney scarring. This result may shed light on the immunopathogenesis of lupus nephritis.</description><subject>activity index</subject><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Chemokine CCL2 - analysis</subject><subject>Chemokine CCL2 - urine</subject><subject>chronicity index</subject><subject>Cytokines</subject><subject>Cytokines - analysis</subject><subject>Cytokines - urine</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>double strand</subject><subject>Extended Report</subject><subject>Female</subject><subject>GATA3 Transcription Factor - analysis</subject><subject>GATA3 Transcription Factor - urine</subject><subject>Gene expression</subject><subject>Gene Expression - genetics</subject><subject>Gene Expression - immunology</subject><subject>Genetic engineering</subject><subject>Humans</subject><subject>IFN</subject><subject>interferon</subject><subject>Interferon-gamma - analysis</subject><subject>Interferon-gamma - urine</subject><subject>interleukin</subject><subject>Interleukins - analysis</subject><subject>Interleukins - urine</subject><subject>Kidney - immunology</subject><subject>Kidney - pathology</subject><subject>Kidney diseases</subject><subject>Kidney Glomerulus - immunology</subject><subject>Kidney Glomerulus - pathology</subject><subject>Kidney Tubules - immunology</subject><subject>Kidney Tubules - pathology</subject><subject>Kidneys</subject><subject>Lasers</subject><subject>Leukocytes - immunology</subject><subject>Lupus</subject><subject>Lupus Nephritis - genetics</subject><subject>Lupus Nephritis - immunology</subject><subject>Lupus Nephritis - pathology</subject><subject>Male</subject><subject>MCP</subject><subject>Medical sciences</subject><subject>messenger RNA</subject><subject>Methods</subject><subject>monocyte chemoattractant protein</subject><subject>mRNA</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Polyethylene</subject><subject>real-time quantitative PCR</subject><subject>ribosomal RNA</subject><subject>Rodents</subject><subject>rRNA</subject><subject>RT-QPCR</subject><subject>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</subject><subject>SLE</subject><subject>SLEDAI</subject><subject>Studies</subject><subject>systemic lupus erythematosus</subject><subject>Systemic Lupus Erythematosus Disease Activity Index</subject><subject>T-Box Domain Proteins - analysis</subject><subject>T-Box Domain Proteins - urine</subject><subject>Transcription factors</subject><subject>Transforming Growth Factor beta - analysis</subject><subject>Transforming Growth Factor beta - urine</subject><subject>Urinary system involvement in other diseases. Miscellaneous</subject><subject>WHO</subject><subject>World Health Organization</subject><issn>0003-4967</issn><issn>1468-2060</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqF0b9v1DAUB3ALgehRmNlQJESHSrk-2_GPLEjoVGilU2EoDCyW47y0vuaS1E5Q-9_jU04tdOliy_bHT8_-EvKewpJSLk9sqJcMQC5Bcsr4C7KghdQ5AwkvyQIAeF6UUh2QNzFu0hI01a_JAVWc7fYXRJ53Y7ABO9tm7n7sb3yH2RWmAe-GgDH6vst8l7XTMMWsw-E6-NHHt-RVY9uI7_bzIfn59fRydZavv387X31Z55UQfMxZI6CoNLNIEZkDi4Lr2lWMUe2kLnhBAasG65KColIL19BacdEwW4CtS35IPs91h6naYu1w121rhuC3Ntyb3nrz_0nnr81V_8fQUgjKWCpwtC8Q-tsJ42i2PjpsW9thP0WjQCYqxbOQlloKISHBj0_gpp9C-r9klFJaUKl4UiezcqGPMWDz0DMFs4vOpOjMLjozR5dufPj3qY9-n1UCn_bARmfbJtjO-fjotGaCCZlcPjsfR7x7OLfhxqQqSpiLX6v0nEtRyt8_zDr549lX282zXf4FsmS9cw</recordid><startdate>20070701</startdate><enddate>20070701</enddate><creator>Chan, Rebecca Wing-Yan</creator><creator>Lai, Fernand Mac-Moune</creator><creator>Li, Edmund Kwok-Ming</creator><creator>Tam, Lai-Shan</creator><creator>Chow, Kai-Ming</creator><creator>Lai, Ka-Bik</creator><creator>Li, Philip Kam-Tao</creator><creator>Szeto, Cheuk-Chun</creator><general>BMJ Publishing Group Ltd and European League Against Rheumatism</general><general>BMJ</general><general>BMJ Publishing Group LTD</general><general>BMJ Group</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>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20070701</creationdate><title>Intrarenal cytokine gene expression in lupus nephritis</title><author>Chan, Rebecca Wing-Yan ; Lai, Fernand Mac-Moune ; Li, Edmund Kwok-Ming ; Tam, Lai-Shan ; Chow, Kai-Ming ; Lai, Ka-Bik ; Li, Philip Kam-Tao ; Szeto, Cheuk-Chun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b553t-2f504b82ae1ee2c0ae538dcb2218c6843410ebfed91071685cf1d735f2a40ad93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>activity index</topic><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Chemokine CCL2 - analysis</topic><topic>Chemokine CCL2 - urine</topic><topic>chronicity index</topic><topic>Cytokines</topic><topic>Cytokines - analysis</topic><topic>Cytokines - urine</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>double strand</topic><topic>Extended Report</topic><topic>Female</topic><topic>GATA3 Transcription Factor - analysis</topic><topic>GATA3 Transcription Factor - urine</topic><topic>Gene expression</topic><topic>Gene Expression - genetics</topic><topic>Gene Expression - immunology</topic><topic>Genetic engineering</topic><topic>Humans</topic><topic>IFN</topic><topic>interferon</topic><topic>Interferon-gamma - analysis</topic><topic>Interferon-gamma - urine</topic><topic>interleukin</topic><topic>Interleukins - analysis</topic><topic>Interleukins - urine</topic><topic>Kidney - immunology</topic><topic>Kidney - pathology</topic><topic>Kidney diseases</topic><topic>Kidney Glomerulus - immunology</topic><topic>Kidney Glomerulus - pathology</topic><topic>Kidney Tubules - immunology</topic><topic>Kidney Tubules - pathology</topic><topic>Kidneys</topic><topic>Lasers</topic><topic>Leukocytes - immunology</topic><topic>Lupus</topic><topic>Lupus Nephritis - genetics</topic><topic>Lupus Nephritis - immunology</topic><topic>Lupus Nephritis - pathology</topic><topic>Male</topic><topic>MCP</topic><topic>Medical sciences</topic><topic>messenger RNA</topic><topic>Methods</topic><topic>monocyte chemoattractant protein</topic><topic>mRNA</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Polyethylene</topic><topic>real-time quantitative PCR</topic><topic>ribosomal RNA</topic><topic>Rodents</topic><topic>rRNA</topic><topic>RT-QPCR</topic><topic>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</topic><topic>SLE</topic><topic>SLEDAI</topic><topic>Studies</topic><topic>systemic lupus erythematosus</topic><topic>Systemic Lupus Erythematosus Disease Activity Index</topic><topic>T-Box Domain Proteins - analysis</topic><topic>T-Box Domain Proteins - urine</topic><topic>Transcription factors</topic><topic>Transforming Growth Factor beta - analysis</topic><topic>Transforming Growth Factor beta - urine</topic><topic>Urinary system involvement in other diseases. 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Aim: To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis. Methods: 36 consecutive patients with systemic lupus erythematosus having active renal disease were recruited, and they were required to undergo kidney biopsy. Glomerular and tubulointestitial cytokine expression of interleukin (IL)2, 4, 10, 12, 18, interferon γ (IFN)γ, T-bet (the Th1 transcription factor), GATA-3 (the Th2 transcription factor), transforming growth factorβ and monocyte chemoattractant protein (MCP)1 were studied by laser microdissection of the renal biopsy specimen, followed by real-time quantitative PCR. Results: There were 13 patients with World Health Organization class III nephritis, 14 patients with class IV nephritis and 9 patients with class V nephritis. There was a significant correlation between serum C3, C4 and anti-double strand DNA antibody level with glomerular expression of T-bet, IFNγ and IL2. There was a significant correlation between histological activity index and glomerular expression of IL12, IL18, IL10 and MCP1. In addition, the degree of glomerular leucocyte infiltration significantly correlated with glomerular expression of IFNγ, IL10, IL12 and IL18. By contrast, histological chronicity index correlated with the tubulointerstitial expression of IL2, MCP1 and GATA-3. Conclusions: Intraglomerular expression of certain target genes correlate with the severity of systemic as well as histological activity, whereas the tubulointerstitial expression of other target genes correlate with the degree of chronic kidney scarring. This result may shed light on the immunopathogenesis of lupus nephritis.</abstract><cop>London</cop><pub>BMJ Publishing Group Ltd and European League Against Rheumatism</pub><pmid>17324967</pmid><doi>10.1136/ard.2006.063123</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; BMJ Journals - NESLi2; PubMed Central; EZB Electronic Journals Library
subjects activity index
Adult
Biological and medical sciences
Chemokine CCL2 - analysis
Chemokine CCL2 - urine
chronicity index
Cytokines
Cytokines - analysis
Cytokines - urine
Deoxyribonucleic acid
DNA
double strand
Extended Report
Female
GATA3 Transcription Factor - analysis
GATA3 Transcription Factor - urine
Gene expression
Gene Expression - genetics
Gene Expression - immunology
Genetic engineering
Humans
IFN
interferon
Interferon-gamma - analysis
Interferon-gamma - urine
interleukin
Interleukins - analysis
Interleukins - urine
Kidney - immunology
Kidney - pathology
Kidney diseases
Kidney Glomerulus - immunology
Kidney Glomerulus - pathology
Kidney Tubules - immunology
Kidney Tubules - pathology
Kidneys
Lasers
Leukocytes - immunology
Lupus
Lupus Nephritis - genetics
Lupus Nephritis - immunology
Lupus Nephritis - pathology
Male
MCP
Medical sciences
messenger RNA
Methods
monocyte chemoattractant protein
mRNA
Nephrology. Urinary tract diseases
Polyethylene
real-time quantitative PCR
ribosomal RNA
Rodents
rRNA
RT-QPCR
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
SLE
SLEDAI
Studies
systemic lupus erythematosus
Systemic Lupus Erythematosus Disease Activity Index
T-Box Domain Proteins - analysis
T-Box Domain Proteins - urine
Transcription factors
Transforming Growth Factor beta - analysis
Transforming Growth Factor beta - urine
Urinary system involvement in other diseases. Miscellaneous
WHO
World Health Organization
title Intrarenal cytokine gene expression in lupus nephritis
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-13T18%3A00%3A28IST&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=Intrarenal%20cytokine%20gene%20expression%20in%20lupus%20nephritis&rft.jtitle=Annals%20of%20the%20rheumatic%20diseases&rft.au=Chan,%20Rebecca%20Wing-Yan&rft.date=2007-07-01&rft.volume=66&rft.issue=7&rft.spage=886&rft.epage=892&rft.pages=886-892&rft.issn=0003-4967&rft.eissn=1468-2060&rft.coden=ARDIAO&rft_id=info:doi/10.1136/ard.2006.063123&rft_dat=%3Cproquest_pubme%3E4008407731%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1777851673&rft_id=info:pmid/17324967&rfr_iscdi=true