Effect of treatment of rheumatoid arthritis with infliximab on IFNγ, IL4, T-bet, and GATA-3 expression: link with improvement of systemic inflammation and disease activity

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Abstract
Objective: To study interferon γ (IFNγ) 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. IFNγ concentrations in supernatants were determined by ELISA. mRNA expression of IFNγ, 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 IFNγ production and in the response to Th1 inducing cytokines occurred in rheumatoid PBMC. Reduction of systemic inflammation with infliximab treatment increased IFNγ production in response to IL12 or IL12+IL18. The IFNγ/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 IFNγ and IL4 expression appeared different. The IFNγ/IL4 ratio might express the blood Th1/Th2 balance better than the T-bet/GATA-3 ratio. Reduced IFNγ production by rheumatoid PBMC and levels of IFNγ and IL4 mRNA expression in blood were linked to disease improvement, indicating an association between this systemic Th1 feature and disease activity.

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