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J Biol Chem, Vol. 273, Issue 46, 30410-30414, November 13, 1998
From the Departments of Immunology and Vascular Biology, The
Scripps Research Institute, La Jolla, California 92037 and
Mononuclear phagocytes play a major role in
immune and inflammatory responses. Bacterial lipopolysaccharide (LPS)
induces monocytes to express a variety of genes by activating the
NF-
Role of IKK1 and IKK2 in Lipopolysaccharide Signaling in
Human Monocytic Cells
,,, and Signal Pharmaceuticals Inc., San
Diego, California 92121
B/Rel transcription factor family. Recently, we have reported
that the tumor necrosis factor and interleukin 1 signaling pathways
activate two kinases, IKK1 and IKK2. Phosphorylation of the IB
cytoplasmic inhibitors, IB
, IB
, and IB
, by these
kinases triggers proteolytic degradation and the release of NF-B/Rel
proteins into the nucleus. At present, the role of the IKKs in LPS
signaling has not been investigated. Here, we report that LPS induces
IKK activity in human monocytes and THP-1 monocytic cells. The kinetics
of activation of kinase activity in monocytic cells are relatively slow
with maximal activity observed at 60 min, which coincides with the degradation of IBs and the nuclear translocation of NF-B. In transfection experiments, overexpression of wild type IKK1, a dominant
negative mutant IKK1 (K44M), or wild type IKK2 did not affect
LPS-induced B-dependent transcription in monocytic
cells. In contrast, a dominant negative mutant of IKK2 inhibited LPS induction of B-dependent transcription in a
dose-dependent manner. These results indicate that LPS
induction of B-dependent gene expression in human
monocytic cells requires activation of IKK2.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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