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-␣). TNF-␣ 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-␣ gene transcription or TNF-␣ 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-␣, 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 SAPK␤, SAPK␤ K-A, blocked translation of TNF-␣, as determined by using a TNF-␣ translational reporting system. Finally, overexpression of wild-type SAPK␤ was able to overcome the dexamethasone-induced block of TNF-␣ 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-␣ mRNA. A novel mechanism by which dexamethasone inhibits translation of TNF-␣ is also revealed.

Anti‐inflammatory and anti‐insulin resistance activities of aqueous extract from Anoectochilus burmannicus

“…Significantly, lycopene attenuated the effects of LPS by inhibiting a key inflammatory pathway related to mitogen‐activated protein kinase (MAPK), ERK1/2 and p38 MAPK, and NF‐κB, but not JNK (Feng et al., 2010). This observation supports the hypothesis that ERK1/2 predominantly triggers the expression of IL‐1β and IL‐6, whereas JNK is the main transduction pathway of TNF‐α, after LPS stimulation (Swantek, Cobb, & Geppert, 1997). It is possible that ABE may inhibit the LPS activation of MAPK and NF‐kB pathways leading to the decrease in IL‐1β and IL‐6.…”

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

“…Phosphorylation and activation of MAPKs have been shown to be relevant to the regulation of cytokine production, especially TNF␣ production, at both the transcriptional and translational levels (25)(26)(27)(28)(29). We therefore investigated the phosphorylation of MAPKs in CD14ϩ synovial cells stimulated with IFN␥ alone, with rsCD154 alone, or with rsCD154 plus IFN␥, using Western blotting probed with phosphorylation-site-specific antibodies.…”

Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms

“…JNK, as well as p38, mediates cytokine-induced production of TNF␣, and the inhibition of JNK activity was shown to be involved in glucocorticoid-induced inhibition of the translation of TNF␣ messenger RNA (31). Moreover, the MAP kinase kinases MKK-4 and MKK-7, which are upstream activators of JNK-2, are highly expressed in RA synovium (32) and are constitutively expressed in cultured RA synovial fibroblasts, where they form a stable functional "signalsome" complex with JNK-2 (33).…”