p38-dependent c-Jun degradation contributes to reduced PGE2 production in sodium orthovanadate-treated macrophages
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In particular, the phenomenon of c-Jun degradation within theinflammatory response has not yet been fully analyzed. In orderto verify this, we investigated LPS-stimulated murine macrophagespre-treated with sodium orthovanadate (SO) in order to uncoverthe regulatory mechanisms of the MAPKs which regulate c-Jundegradation within the inflammatory response. Through our study,we found that SO suppressed the production of prostaglandinE2 (PGE2) and the expression of COX-2 in LPS-stimulated RAW264.7cells. Additionally, SO decreased total c-Jun levels, withoutaltering the amount of mRNA, although the phospho-levels ofp38, ERK, and JNK were strongly enhanced. Through the usageof selective MAPK inhibitors, and knockdown and overexpressionstrategies, p38 was revealed to be a major MAPK which regulatesc-Jun degradation. Further analysis indicates that the phosphorylationof p38 is a determinant for c-Jun degradation, andis sufficient to induce ubiquitination-dependent c-Jun degradation,recovered through MG132 treatment. Therefore, our results suggestthat the hyperphosphorylation of p38 by SO contributesto c-Jun degradation, which is linked to the suppression of PGE2secretion in inflammatory responses; and thus, finding drugs toincrease p38 activity could be a novel strategy for the developmentof anti-inflammatory drugs.
Abstract
In particular, the phenomenon of c-Jun degradation within theinflammatory response has not yet been fully analyzed. In orderto verify this, we investigated LPS-stimulated murine macrophagespre-treated with sodium orthovanadate (SO) in order to uncoverthe regulatory mechanisms of the MAPKs which regulate c-Jundegradation within the inflammatory response. Through our study,we found that SO suppressed the production of prostaglandinE2 (PGE2) and the expression of COX-2 in LPS-stimulated RAW264.7cells. Additionally, SO decreased total c-Jun levels, withoutaltering the amount of mRNA, although the phospho-levels ofp38, ERK, and JNK were strongly enhanced. Through the usageof selective MAPK inhibitors, and knockdown and overexpressionstrategies, p38 was revealed to be a major MAPK which regulatesc-Jun degradation. Further analysis indicates that the phosphorylationof p38 is a determinant for c-Jun degradation, andis sufficient to induce ubiquitination-dependent c-Jun degradation,recovered through MG132 treatment. Therefore, our results suggestthat the hyperphosphorylation of p38 by SO contributesto c-Jun degradation, which is linked to the suppression of PGE2secretion in inflammatory responses; and thus, finding drugs toincrease p38 activity could be a novel strategy for the developmentof anti-inflammatory drugs.
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