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J Biol Chem, Vol. 274, Issue 12, 7611-7614, March 19, 1999
B
through Interleukin-1 Signaling Mediators in Cultured Human Dermal
Endothelial Cells and Mononuclear Phagocytes
,
,,,
From the Bacterial lipopolysaccharide
(LPS)-mediated immune responses, including activation of monocytes,
macrophages, and endothelial cells, play an important role in the
pathogenesis of Gram-negative bacteria-induced sepsis syndrome.
Activation of NF- Division of Pediatric Infectious Diseases, Division of Cardiology and the Burns and Allen
Research Institute, Cedars-Sinai Medical Center and UCLA School of
Medicine, Los Angeles, California 90048, § Tularik Inc.,
South San Francisco, California 98080, and the ¶ Department of
Immunology and Cell Biology, Mario Negri Institute, I-20157 Milan,
Italy
B is thought to be required for cytokine release
from LPS-responsive cells, a critical step for endotoxic effects. Here
we investigated the role and involvement of interleukin-1 (IL-1) and
tumor necrosis factor (TNF-
) signal transducer molecules in LPS
signaling in human dermal microvessel endothelial cells (HDMEC) and
THP-1 monocytic cells. LPS stimulation of HDMEC and THP-1 cells
initiated an IL-1 receptor-like NF-B signaling cascade. In transient
cotransfection experiments, dominant negative mutants of the IL-1
signaling pathway, including MyD88, IRAK, IRAK2, and TRAF6 inhibited
both IL-1- and LPS-induced NF-B-luciferase activity. LPS-induced
NF-B activation was not inhibited by a dominant negative mutant of
TRAF2 that is involved in TNF signaling. LPS-induced activation of
NF-B-responsive reporter gene was not inhibited by IL-1 receptor
antagonist. TLR2 and TLR4 were expressed on the cell surface of HDMEC
and THP-1 cells. These findings suggest that a signal transduction
molecule in the LPS receptor complex may belong to the IL-1
receptor/toll-like receptor (TLR) super family, and the LPS signaling
cascade uses an analogous molecular framework for signaling as IL-1
in mononuclear phagocytes and endothelial cells.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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