Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
Correspondence: Yoshihiro Ohmori, D.D.S., Ph.D., Department of Immunology, NB30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Email: ohmorih{at}ccf.org
This study examines the role of the signal transducer and activator of
transcription 1 (STAT1) in induction of lipopolysaccharide
(LPS)-stimulated gene expression both in vitro and in vivo. LPS-induced
expression of an interferon (IFN)-inducible 10-kDa protein (IP-10), IFN
regulatory factor-1 (IRF-1), and inducible nitric oxide synthase (iNOS)
mRNAs was severely impaired in macrophages prepared from
Stat1-/- mice, whereas levels of tumor necrosis factor
and KC (a C-X-C chemokine) mRNA in LPS-treated cell cultures were
unaffected. A similar deficiency in LPS-induced gene expression was
observed in livers and spleens from Stat1-/- mice. The
reduced LPS-stimulated gene expression seen in Stat1-/-
macrophages was not the result of reduced activation of nuclear factor
B. LPS stimulated the delayed activation of both IFN-stimulated
response element and IFN-
-activated sequence binding activity in
macrophages from wild-type mice. Activation of these STAT1-containing
transcription factors was mediated by the intermediate induction of
type I IFNs, since the LPS-induced IP-10, IRF-1, and iNOS mRNA
expression was markedly reduced in macrophages from
IFN-/ßR-/- mice and blocked by cotreatment with
antibodies against type I IFN. These results indicate that indirect
activation of STAT1 by LPS-induced type I IFN participates in promoting
optimal expression of LPS-inducible genes, and they suggest that STAT1
may play a critical role in innate immunity against gram-negative
bacterial infection.
Key Words: transcriptional regulation • type I IFNs
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