The Fli‐1 transcription factor is implicated in the pathogenesis of systemic lupus erythematosus (SLE), both in humans and in animal models. Dysregulation of interleukin‐6 (IL‐6) is also associated with SLE. The purpose of this study was to investigate whether Fli‐1 directly regulates the expression of IL‐6.

Sera were collected from wild‐type and Fli‐1–heterozygous (Fli‐1^+/−) MRL/lpr mice, and the concentration of IL‐6 was measured by enzyme‐linked immunosorbent assay (ELISA). Expression of IL‐6 in the kidney was measured by real‐time polymerase chain reaction analysis. T cells were isolated from wild‐type and Fli‐1^+/− MRL/lpr mice and stimulated with CD3/CD28 beads, and the concentration of IL‐6 in the supernatants was measured by ELISA. MS1 endothelial cells were transfected with Fli‐1 and control small interfering RNA, and the production of IL‐6 was compared after lipopolysaccharide stimulation. A chromatin immunoprecipitation (ChIP) assay was performed to determine whether Fli‐1 binds to the IL‐6 promoter region. Transient transfections with the NIH3T3 cell line were performed to examine whether Fli‐1 regulates the expression of IL‐6.

Fli‐1^+/− MRL/lpr mice had significantly decreased IL‐6 levels in sera and reduced expression of IL‐6 in kidneys as compared to their wild‐type littermates. T cells isolated from Fli‐1^+/− MRL/lpr mice produced less IL‐6 than did those from wild‐type mice. Inhibiting the expression of Fli‐1 in endothelial cells resulted in reduced production of IL‐6. The ChIP assay revealed direct binding of Fli‐1 to 3 regions within the IL‐6 promoter. Fli‐1 activated transcription from the IL‐6 promoter in a dose‐dependent manner.

The direct regulation of IL‐6 expression by Fli‐1 represents one possible mechanism for the protective effect of decreased Fli‐1 expression in lupus.