Effect of treatment of rheumatoid arthritis with infliximab on IFN gamma, IL4, T-bet, and GATA-3 expression: link with improvement of systemic inflammation and disease activity.
OBJECTIVE
To study interferon gamma (IFN gamma) production and the expression of T-bet and GATA-3, the transcription factors associated with Th1 and Th2, in peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis before and during infliximab treatment, so as to distinguish between a disease specific and a disease activity dependent defect.


METHODS
Rheumatoid PBMC were obtained at weeks 0 and 6 of infliximab treatment and cultured for seven days with or without interleukin (IL)12 or the combination of IL12 and IL18. IFN gamma concentrations in supernatants were determined by ELISA. mRNA expression of IFN gamma, IL4, T-bet, and GATA-3 was determined by real time RT-PCR in whole blood at weeks 0 and 22.


RESULTS
A reduction in spontaneous IFN gamma production and in the response to Th1 inducing cytokines occurred in rheumatoid PBMC. Reduction of systemic inflammation with infliximab treatment increased IFN gamma production in response to IL12 or IL12+IL18. The IFN gamma/IL4 expression ratio of rheumatoid blood before treatment was lower than in healthy controls but was increased by infliximab treatment. T-bet expression or T-bet/GATA-3 ratio of rheumatoid blood was less than in controls. The T-bet/GATA-3 ratio was not influenced by infliximab treatment.


CONCLUSIONS
Regulation of T-bet and GATA-3 or IFN gamma and IL4 expression appeared different. The IFN gamma/IL4 ratio might express the blood Th1/Th2 balance better than the T-bet/GATA-3 ratio. Reduced IFN gamma production by rheumatoid PBMC and levels of IFN gamma and IL4 mRNA expression in blood were linked to disease improvement, indicating an association between this systemic Th1 feature and disease activity.
Department of Immunology and Rheumatology, INSERM U-403, Hospital Edouard Herriot, 69437 Lyon Cedex 03, France.
M
M
Kawashima
P
P
Miossec
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000069285:Infliximab; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome; D000098815:T-bet Transcription Factor
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma; D000069285:Infliximab