TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway

Calin D. Dumitru; Jeffrey D. Ceci; Christos Tsatsanis; Dimitris Kontoyiannis; Konstantinos Stamatakis; Jun Hsiang Lin; Christos Patriotis; Nancy A. Jenkins; Neal G. Copeland; George Kollias; Philip N. Tsichlis

doi:10.1016/S0092-8674(00)00210-5

TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway

Calin D. Dumitru, Jeffrey D. Ceci, Christos Tsatsanis, Dimitris Kontoyiannis, Konstantinos Stamatakis, Jun Hsiang Lin, Christos Patriotis, Nancy A. Jenkins, Neal G. Copeland, George Kollias, Philip N. Tsichlis

Research output: Contribution to journal › Article

659 Scopus citations

Abstract

Tpl2 knockout mice produce low levels of TNF-α 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-κB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-α 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-α mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-α. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport, of TNF-α mRNA from the nucleus to the cytoplasm.

Original language	English (US)
Pages (from-to)	1071-1083
Number of pages	13
Journal	Cell
Volume	103
Issue number	7
DOIs	https://doi.org/10.1016/S0092-8674(00)00210-5
State	Published - Dec 22 2000

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. / Dumitru, Calin D.; Ceci, Jeffrey D.; Tsatsanis, Christos; Kontoyiannis, Dimitris; Stamatakis, Konstantinos; Lin, Jun Hsiang; Patriotis, Christos; Jenkins, Nancy A.; Copeland, Neal G.; Kollias, George; Tsichlis, Philip N.

In: Cell, Vol. 103, No. 7, 22.12.2000, p. 1071-1083.

Research output: Contribution to journal › Article

Dumitru, Calin D. ; Ceci, Jeffrey D. ; Tsatsanis, Christos ; Kontoyiannis, Dimitris ; Stamatakis, Konstantinos ; Lin, Jun Hsiang ; Patriotis, Christos ; Jenkins, Nancy A. ; Copeland, Neal G. ; Kollias, George ; Tsichlis, Philip N. / TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. In: Cell. 2000 ; Vol. 103, No. 7. pp. 1071-1083.

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title = "TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway",

abstract = "Tpl2 knockout mice produce low levels of TNF-α 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-κB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-α 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-α mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-α. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport, of TNF-α mRNA from the nucleus to the cytoplasm.",

author = "Dumitru, {Calin D.} and Ceci, {Jeffrey D.} and Christos Tsatsanis and Dimitris Kontoyiannis and Konstantinos Stamatakis and Lin, {Jun Hsiang} and Christos Patriotis and Jenkins, {Nancy A.} and Copeland, {Neal G.} and George Kollias and Tsichlis, {Philip N.}",

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AU - Dumitru, Calin D.

AU - Ceci, Jeffrey D.

AU - Tsatsanis, Christos

AU - Kontoyiannis, Dimitris

AU - Stamatakis, Konstantinos

AU - Lin, Jun Hsiang

AU - Patriotis, Christos

AU - Jenkins, Nancy A.

AU - Copeland, Neal G.

AU - Kollias, George

AU - Tsichlis, Philip N.

PY - 2000/12/22

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N2 - Tpl2 knockout mice produce low levels of TNF-α 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-κB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-α 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-α mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-α. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport, of TNF-α mRNA from the nucleus to the cytoplasm.

AB - Tpl2 knockout mice produce low levels of TNF-α 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-κB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-α 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-α mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-α. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport, of TNF-α mRNA from the nucleus to the cytoplasm.

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