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and IFN-
in Macrophages1
,
,
Departments of
* Medicine,
Biochemistry and Molecular Biology, and
Critical Care Medicine, and
Immunology Research Group, University of Calgary, Calgary, Alberta, Canada
Complement factor B (Bf) plays an important role in activating the
alternative complement pathway. The inflammatory cytokines, in
particular TNF-
and IFN-
, are critical in the regulation of
Bf gene expression in macrophages. In this study,
we investigated the mechanisms of Bf gene regulation by
TNF- and IFN- in murine macrophages. Northern analysis revealed
that Bf mRNA expression was synergistically up-regulated
by TNF- and IFN- in MH-S cells. Truncations of the 5'
Bf promoter identified a region between -556 and -282 bp
that mediated TNF- responsiveness as well as the synergistic effect
of TNF- and IFN- on Bf expression. Site-directed
mutagenesis of a NF-
B-binding element in this region (-433 to -423
bp) abrogated TNF- responsiveness and decreased the synergistic
effect of TNF- and IFN- on Bf expression. EMSAs
revealed nuclear protein binding to this NF-B
cis-binding element on TNF- stimulation. Supershift
analysis revealed that both p50 and p65 proteins contribute to
induction of Bf by TNF-. An I-B dominant negative
mutant blocked Bf induction by TNF- and reduced the
synergistic induction by TNF- and IFN-. In addition, the
proteasome inhibitor MG132, which blocks NF-B induction, blocked
TNF--induced Bf promoter activity and the synergistic
induction of Bf promoter activity by TNF- and IFN-.
LPS was found to induce Bf promoter activity through the
same NF-B cis-binding site. These findings suggest
that a NF-B cis-binding site between -433 and -423
bp is required for TNF- responsiveness and for TNF-- and
IFN--stimulated synergistic responsiveness of the Bf
gene.
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