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

Research output: Contribution to journalArticle

441 Scopus citations

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
DOIs
StatePublished - Nov 1997

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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