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Department of Cell Biology, University of Alabama, Birmingham, AL 35294
CD40 is a type I membrane-bound molecule belonging to the TNFR
superfamily that is expressed on various immune cells including
macrophages and microglia. The aberrant expression of CD40 is involved
in the initiation and maintenance of various human diseases including
multiple sclerosis, arthritis, atherosclerosis, and Alzheimer’s
disease. Inhibition of CD40 signaling has been shown to provide a
significant beneficial effect in a number of animal models of human
diseases including the aforementioned examples. We have previously
shown that IFN-
induces CD40 expression in macrophages and
microglia. IFN- leads to STAT-1
activation directly and
up-regulation of NF-
B activity due to the secretion and subsequent
autocrine signaling of TNF-. However, TNF- alone is not capable
of inducing CD40 expression in these cells. Suppressor
of cytokine signaling 1 protein (SOCS-1) is a cytokine-inducible Src
homology 2-containing protein that regulates cytokine receptor
signaling by inhibiting STAT-1 activation via a specific interaction
with activated Janus kinase 2. Given the important role of CD40 in
inflammatory events in the CNS as well as other organ systems, it is
imperative to understand the molecular mechanisms contributing to both
CD40 induction and repression. We show that ectopic expression of
SOCS-1 abrogates IFN--induced CD40 protein expression, mRNA levels,
and promoter activity. Additionally, IFN--induced TNF- secretion,
as well as STAT-1 and NF-B activation, are inhibited in the
presence of SOCS-1. We conclude that SOCS-1 inhibits cytokine-induced
CD40 expression by blocking IFN--mediated STAT-1 activation,
which also then results in suppression of IFN--induced TNF-
secretion and subsequent NF-B activation.
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