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B-Inducing Kinase Is Dispensable for Activation of NF-B in Inflammatory Settings but Essential for Lymphotoxin 
Receptor Activation of NF-B in Primary Human Fibroblasts1
*
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, Hammersmith, London, United Kingdom; and
Royal Free Hospital, Hampstead, London, United Kingdom
The transcription factor NF-
B is of major importance in the
biology of pro-inflammatory cytokines, such as TNF-
and
IL-1, and thereby is intimately involved in the process of
inflammation. Understanding the mechanisms by which NF-B is
activated in response to inflammatory stimuli has become a major goal
of inflammation research. The discovery of NF-B-inducing kinase
(NIK) as a TNFR-associated factor-interacting enzyme and a potential
activator of the IB-kinase complex appeared to have identified an
important element of the NF-B activition pathway, a view that was
supported by several subsequent studies. However, recent experiments in
the alymphoplasia (aly/aly) mouse, which has missense
point mutation (G885R) in NIK, has challenged that view. The reasons
for the discrepancy between the different studies is unclear and could
be due to multiple factors, such as cell type, species of cell, or
primary vs transformed cell lines. One system that has not been
investigated is primary human cells. Using an adenoviral vector
encoding kinase-deficient NIK, we have investigated the role of NIK in
LPS, IL-1, TNF-, and lymphotoxin (LT) 
R signaling in
primary human cells and TNF- expression from rheumatoid tissue.
These data show that, in the primary systems tested, NIK has a
restricted role in LTR signaling and is not required by the other
stimuli tested. Also, there is no apparent role for NIK in the process
of TNF- production in human rheumatoid arthritis. These data also
highlight the potential problems in extrapolating the function of
signaling pathways between primary and transfected cell
lines.
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