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*
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037;
Center of Molecular Medicine, Sun Yat-Sen University of Medical Science, Guangzhou, China; and
Novartis Pharma, Basel, Switzerland
Stimulating macrophages with bacterial endotoxin (LPS) activates
numerous intracellular signaling pathways that lead to the production
of TNF. In this study, we show that four mitogen-activated protein
(MAP) kinase pathways are activated in LPS-stimulated macrophages: the
extracellular signal-regulated kinase (ERK), c-Jun N-terminal
kinase/stress-activated protein kinase, p38, and Big MAP kinase
(BMK)/ERK5 pathways. Although specific activation of a single MAP
kinase pathway produces only a modest effect on TNF promoter
activation, activation of each MAP kinase pathway is important for full
induction of the TNF gene. Interestingly, a dramatic induction of TNF
promoter-driven gene expression was observed when all of the four MAP
kinase pathways were activated simultaneously, suggesting a cooperative
effect among these kinases. Unexpectedly, cis elements
known to be targeted by MAP kinases do not play a major role in
multiple MAP kinase-induced TNF gene expression. Rather, a 40-bp
sequence harboring the TATA box, is responsible for the gene
up-regulation induced by MAP kinases. The proximity of the MAP
kinase-responsive element to the transcriptional initiation site
suggested that MAP kinases regulate the transcriptional initiation
complex. Utilizing 
-amanitin-resistant RNA polymerase II mutants
with or without a C-terminal domain (CTD) deletion, we found that
deleting the CTD to 31 tandem repeats (
31) led to >90% reduction
in MAP kinase-mediated TNF production. Thus, our data demonstrate
coordination of multiple MAP kinase pathways in TNF production and
suggest that the CTD of RNA polymerase II is required to execute MAP
kinase signaling in TNF expression.
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