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ERK MAP Kinases Are Critical for the Expression of MKP‐1 and MKP‐2 in Macrophages Following LPS Stimulation
Author(s) -
Liu Yusen,
Xue Jianjing,
Shakibi Yasaman,
Xu Pingping,
Wancket Lyn M.,
Nelin Leif D.,
Frazier W. Joshua
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.831.20
Subject(s) - mapk/erk pathway , p38 mitogen activated protein kinases , kinase , creb , mitogen activated protein kinase , phosphorylation , biology , microbiology and biotechnology , stimulation , protein kinase a , signal transduction , cancer research , transcription factor , endocrinology , biochemistry , gene
Although the MAP kinase phosphatase (MKP) family plays an important role during host defense, the regulation of MKPs during the immune response is not well understood. We studied the expression of MKP‐1 and MKP‐2 in RAW264.7 macrophages during LPS stimulation. We found that pretreatment of cells with U0126, a pharmacological inhibitor of MEK1/2, substantially decreased MKP‐1 and MKP‐2 mRNA levels in LPS‐stimulated macrophages. In contrast, a p38 MAP kinase inhibitor, SB203580, had little effect on the levels of MKP‐1 and MKP‐2 mRNA. The combination of U0126 and SB203580 resulted in greater decreases in MKP‐1 and MKP‐2 mRNA levels than did U0126 alone, suggesting that p38 contributes to MKP‐1 and MKP‐2 induction in response to LPS. Interestingly, in the absence of LPS, SB203580 enhanced ERK and MEK1/2 activities as well as MKP‐2 mRNA and protein expression, suggesting that p38 negatively regulates the ERK pathway by inhibiting a signaling event upstream of MEK1/2. LPS stimulated a potent CREB phosphorylation through a process dependent on p38, but not ERK, and enhanced the localization of phospho‐CREB to the chromatin of both MKP‐1 and MKP‐2. At the protein level, both MKP‐1 and MKP‐2 underwent robust phosphorylation mediated by ERKs. Taken together, our studies suggest that the ERK pathway plays a predominant role in the regulation of MKP‐1 and MKP‐2 through both transcriptional and post‐translational mechanisms.