A critical role of the transcription factor fli-1 in murine lupus development by
regulation of interleukin-6 expression
#MMPMID25155007
Sato S
; Lennard Richard M
; Brandon D
; Jones Buie JN
; Oates JC
; Gilkeson GS
; Zhang XK
Arthritis Rheumatol
2014[Dec]; 66
(12
): 3436-44
PMID25155007
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OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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