TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway.
Tpl2 knockout mice produce low levels of TNF-alpha when exposed to lipopolysaccharide (LPS) and they are resistant to LPS/D-Galactosamine-induced pathology. LPS stimulation of peritoneal macrophages from these mice did not activate MEK1, ERK1, and ERK2 but did activate JNK, p38 MAPK, and NF-kappaB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-alpha induction by experiments showing that normal murine macrophages treated with the MEK inhibitor PD98059 exhibit a similar defect. Deletion of the AU-rich motif in the TNF-alpha mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-alpha. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport of TNF-alpha mRNA from the nucleus to the cytoplasm.
Dumitru
C D
CD
Kimmel Cancer Center, Department of Microbiology and Immunology, Thomas Jefferson University, 233 S. 10th Street, Philadelphia, PA 19107, USA.
Ceci
J D
JD
Tsatsanis
C
C
Kontoyiannis
D
D
Stamatakis
K
K
Lin
J H
JH
Patriotis
C
C
Jenkins
N A
NA
Copeland
N G
NG
Kollias
G
G
Tsichlis
P N
PN
D020413:3' Untranslated Regions / Q000502:physiology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005688:Galactosamine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000503:physiopathology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013864:Thioglycolates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D020413:3' Untranslated Regions; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse