Feedback control of MKP-1 expression by p38.
Mitogen-activated protein (MAP) kinases play a critical role in innate immune responses to microbial infection through eliciting the biosynthesis of proinflammatory cytokines. MAP phosphatases (MKP)-1 is an archetypical member of the dual-specificity phosphatase family that deactivates MAP kinases. Induction of MKP-1 has been implicated in attenuating the lipopolysaccharide (LPS) and Peptidoglycan (PGN) responses, but how the expression of the MKP-1 is regulated is still not fully understood. Here, we show that inhibition of p38 MAP kinase by specific inhibitor SB 203580 or RNA interference (RNAi) markedly reduced the expression of MKP-1 in LPS or PGN-treated macrophages, which is correlated with prolonged activation of p38 and JNK. Depletion of MAPKAP kinase 2 (MK2), a downstream substrate of p38, by RNAi also inhibited the expression of MKP-1. The mRNA level of MKP-1 is not affected by inhibition of p38, but the expression of MKP-1 is inhibited by treatment of cycloheximide. Thus, p38 MAPK plays a critical role in mediating expression of MKP-1 at a post-transcriptional level. Furthermore, inhibition of p38 by SB 203580 prevented the expression of MKP-1 in LPS-tolerized macrophages, restored the activation of MAP kinases after LPS restimulation. These results indicate a critical role of p38-MK2-dependent induction of MKP-1 in innate immune responses.
Hu
Jun-Hao
JH
Signal Transduction Lab of Institute of Health Sciences, Shanghai Institutes for Biological Sciences [corrected] Chinese Academy of Sciences & [corrected] Shanghai Jiao-Tong University School of Medicine, China.
Chen
Ting
T
Zhuang
Zi-Heng
ZH
Kong
Ling
L
Yu
Ming-Can
MC
Liu
Yusen
Y
Zang
Jing-Wu
JW
Ge
Bao-Xue
BX
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004347:Drug Interactions; D004361:Drug Tolerance; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D025461:Feedback, Physiological; D015971:Gene Expression Regulation, Enzymologic; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D010457:Peptidoglycan / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000099190:MAP-Kinase-Activated Kinase 2
D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D007093:Imidazoles; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D048670:MAP Kinase Kinase 4; D010457:Peptidoglycan; D010749:Phosphoprotein Phosphatases; D011494:Protein Kinases; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C517020:Dusp1 protein, mouse; C093642:SB 203580