Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-α) translation: Glucocorticoids inhibit TNF-α translation by blocking JNK/SAPK

Jennifer L. Swantek, Melanie H. Cobb, Thomas D. Geppert

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Abstract

The adverse effects of lipopolysaccharide (LPS) are mediated primarily by tumor necrosis factor alpha (TNF-α). TNF-α production by LPS-stimulated macrophages is regulated at the levels of both transcription and translation. It has previously been shown that several mitogen-activated protein kinases (MAPKs) are activated in response to LPS. We set out to determine which MAPK signaling pathways are activated in our system and which MAPK pathways are required for TNF-α gene transcription or TNF-α mRNA translation. We confirm activation of the MAPK family members extracellular-signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), as well as activation of the immediate upstream MAPK activators MAPK/ERK kinases 1 and 4 (MEK1 and MEK4). We demonstrate that LPS also activates MEK2, MEK3, and MEK6. Furthermore, we demonstrate that dexamethasone, which inhibits the production of cytokines, including TNF-α, significantly inhibits LPS induction of JNK/SAPK activity but not that of p38, ERK1 and ERK2, or MEK3, MEK4, or MEK6. Dexamethasone also blocks the sorbitol but not anisomycin stimulation of JNK/SAPK activity. A kinase- defective mutant of SAPKβ SAPKβ K-A, blocked translation of TNF-α, as determined by using a TNF-α translational reporting system. Finally, overexpression of wild-type SAPKβ was able to overcome the dexamethasone- induced block of TNF-α translation. These data confirm that three MAPK family members and their upstream activators are stimulated by LPS and demonstrate that JNK/SAPK is required for LPS-induced translation of TNF-α mRNA. A novel mechanism by which dexamethasone inhibits translation of TNF- α is also revealed.

Original languageEnglish (US)
Pages (from-to)6274-6282
Number of pages9
JournalMolecular and Cellular Biology
Volume17
Issue number11
StatePublished - Nov 1997

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Heat-Shock Proteins
Protein Kinases
Glucocorticoids
Lipopolysaccharides
Phosphotransferases
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinases
Dexamethasone
MAP Kinase Kinase 1
Anisomycin
MAP Kinase Kinase 4
Mitogen-Activated Protein Kinase 3
Sorbitol
Mitogen-Activated Protein Kinase 1
Protein Biosynthesis
Macrophages
Cytokines
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

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title = "Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-α) translation: Glucocorticoids inhibit TNF-α translation by blocking JNK/SAPK",
abstract = "The adverse effects of lipopolysaccharide (LPS) are mediated primarily by tumor necrosis factor alpha (TNF-α). TNF-α production by LPS-stimulated macrophages is regulated at the levels of both transcription and translation. It has previously been shown that several mitogen-activated protein kinases (MAPKs) are activated in response to LPS. We set out to determine which MAPK signaling pathways are activated in our system and which MAPK pathways are required for TNF-α gene transcription or TNF-α mRNA translation. We confirm activation of the MAPK family members extracellular-signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), as well as activation of the immediate upstream MAPK activators MAPK/ERK kinases 1 and 4 (MEK1 and MEK4). We demonstrate that LPS also activates MEK2, MEK3, and MEK6. Furthermore, we demonstrate that dexamethasone, which inhibits the production of cytokines, including TNF-α, significantly inhibits LPS induction of JNK/SAPK activity but not that of p38, ERK1 and ERK2, or MEK3, MEK4, or MEK6. Dexamethasone also blocks the sorbitol but not anisomycin stimulation of JNK/SAPK activity. A kinase- defective mutant of SAPKβ SAPKβ K-A, blocked translation of TNF-α, as determined by using a TNF-α translational reporting system. Finally, overexpression of wild-type SAPKβ was able to overcome the dexamethasone- induced block of TNF-α translation. These data confirm that three MAPK family members and their upstream activators are stimulated by LPS and demonstrate that JNK/SAPK is required for LPS-induced translation of TNF-α mRNA. A novel mechanism by which dexamethasone inhibits translation of TNF- α is also revealed.",
author = "Swantek, {Jennifer L.} and Cobb, {Melanie H.} and Geppert, {Thomas D.}",
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T1 - Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-α) translation

T2 - Glucocorticoids inhibit TNF-α translation by blocking JNK/SAPK

AU - Swantek, Jennifer L.

AU - Cobb, Melanie H.

AU - Geppert, Thomas D.

PY - 1997/11

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N2 - The adverse effects of lipopolysaccharide (LPS) are mediated primarily by tumor necrosis factor alpha (TNF-α). TNF-α production by LPS-stimulated macrophages is regulated at the levels of both transcription and translation. It has previously been shown that several mitogen-activated protein kinases (MAPKs) are activated in response to LPS. We set out to determine which MAPK signaling pathways are activated in our system and which MAPK pathways are required for TNF-α gene transcription or TNF-α mRNA translation. We confirm activation of the MAPK family members extracellular-signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), as well as activation of the immediate upstream MAPK activators MAPK/ERK kinases 1 and 4 (MEK1 and MEK4). We demonstrate that LPS also activates MEK2, MEK3, and MEK6. Furthermore, we demonstrate that dexamethasone, which inhibits the production of cytokines, including TNF-α, significantly inhibits LPS induction of JNK/SAPK activity but not that of p38, ERK1 and ERK2, or MEK3, MEK4, or MEK6. Dexamethasone also blocks the sorbitol but not anisomycin stimulation of JNK/SAPK activity. A kinase- defective mutant of SAPKβ SAPKβ K-A, blocked translation of TNF-α, as determined by using a TNF-α translational reporting system. Finally, overexpression of wild-type SAPKβ was able to overcome the dexamethasone- induced block of TNF-α translation. These data confirm that three MAPK family members and their upstream activators are stimulated by LPS and demonstrate that JNK/SAPK is required for LPS-induced translation of TNF-α mRNA. A novel mechanism by which dexamethasone inhibits translation of TNF- α is also revealed.

AB - The adverse effects of lipopolysaccharide (LPS) are mediated primarily by tumor necrosis factor alpha (TNF-α). TNF-α production by LPS-stimulated macrophages is regulated at the levels of both transcription and translation. It has previously been shown that several mitogen-activated protein kinases (MAPKs) are activated in response to LPS. We set out to determine which MAPK signaling pathways are activated in our system and which MAPK pathways are required for TNF-α gene transcription or TNF-α mRNA translation. We confirm activation of the MAPK family members extracellular-signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), as well as activation of the immediate upstream MAPK activators MAPK/ERK kinases 1 and 4 (MEK1 and MEK4). We demonstrate that LPS also activates MEK2, MEK3, and MEK6. Furthermore, we demonstrate that dexamethasone, which inhibits the production of cytokines, including TNF-α, significantly inhibits LPS induction of JNK/SAPK activity but not that of p38, ERK1 and ERK2, or MEK3, MEK4, or MEK6. Dexamethasone also blocks the sorbitol but not anisomycin stimulation of JNK/SAPK activity. A kinase- defective mutant of SAPKβ SAPKβ K-A, blocked translation of TNF-α, as determined by using a TNF-α translational reporting system. Finally, overexpression of wild-type SAPKβ was able to overcome the dexamethasone- induced block of TNF-α translation. These data confirm that three MAPK family members and their upstream activators are stimulated by LPS and demonstrate that JNK/SAPK is required for LPS-induced translation of TNF-α mRNA. A novel mechanism by which dexamethasone inhibits translation of TNF- α is also revealed.

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