Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells.
Engaging mammalian Toll-like receptors (TLRs) activate both the NF-kappaB and mitogen-activated protein kinase signaling pathways. Here we establish that mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands. Despite rescuing TLR-dependent ERK activation in nfkb1(-/-) bone marrow-derived macrophages by using an estrogen receptor-regulated version of the mitogen-activated protein 3 kinase, c-Raf (Raf:ER), CpG or LPS induction of IL-10 was only partially restored in nfkb1(-/-) cells expressing Raf:ER, a finding consistent with NF-kappaB1 regulating IL-10 by a combination of ERK-independent and -dependent mechanisms. Collectively, our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Ashish
A
Banerjee
Raffi
R
Gugasyan
Martin
M
McMahon
Steve
S
Gerondakis
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D048490:raf Kinases / Q000378:metabolism
D003521:Cyclopropanes; D008024:Ligands; D008070:Lipopolysaccharides; C508012:N2-cyclopropylamine-guanosine; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D051193:Toll-Like Receptors; D006151:Guanosine; D016753:Interleukin-10; C073701:Nfkb1 protein, mouse; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse