Overexpression of synoviolin in peripheral blood and synoviocytes from rheumatoid arthritis patients and continued elevation in nonresponders to infliximab treatment.
OBJECTIVE
Synoviolin is a novel E3 ubiquitin ligase that has been implicated in the pathogenesis of rheumatoid arthritis (RA). The purpose of this study was to examine the expression and regulation of synoviolin by tumor necrosis factor alpha (TNFalpha), both in vivo and in vitro.


METHODS
A total of 54 RA patients and 23 healthy control subjects were analyzed before, 4 hours after the first infusion, and at week 22 of infliximab treatment. Clinical response was assessed by the American College of Rheumatology criteria for 20% improvement and the Disease Activity Score in 28 joints (DAS28) at 6 months. Synoviolin messenger RNA expression was measured by real-time reverse transcription-polymerase chain reaction in peripheral blood (PB) and fibroblast-like synoviocytes (FLS) and with and without TNFalpha or interleukin-1beta (IL-1beta) stimulation.


RESULTS
Synoviolin expression was increased in whole PB obtained from RA patients as compared with that from healthy controls and was significantly reduced early and late after infliximab treatment in responders, but in not nonresponders. Reduction in synoviolin expression was associated with reduced levels of markers of disease activity, including C-reactive protein levels. Nonresponders to infliximab therapy had significantly higher synoviolin expression at baseline as compared with responders, and this elevation persisted despite infliximab therapy. PB CD14+ monocytes expressed increased synoviolin levels compared with CD3+ lymphocytes, and TNFalpha or IL-1beta induced a further increase in expression in CD3+ cells. TNFalpha or IL-1beta induced sustained synoviolin expression in RA FLS.


CONCLUSIONS
Elevated PB levels of synoviolin were identified in circulating PB mononuclear cells and were associated with nonresponse to infliximab treatment. Sustained up-regulation of synoviolin by IL-lbeta and TNFalpha may contribute to prolonged survival of immune cells and dysregulated FLS proliferation, leading to RA chronicity.
Toh
Myew-Ling
ML
Unité Mixte Hospices Civils de Lyon-BioMérieux, Hôpital Edouard Herriot, Lyon, France.
Marotte
Hubert
H
Blond
Jean-Luc
JL
Jhumka
Umar
U
Eljaafari
Assia
A
Mougin
Bruno
B
Miossec
Pierre
P
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000069285:Infliximab; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000097:blood* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D000069285:Infliximab; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases