Knockout of Mkp-1 enhances the host inflammatory responses to gram-positive bacteria.
MAPK phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAPK. We have previously demonstrated that MKP-1 acts as a negative regulator of p38 and JNK in immortalized macrophages after stimulation with peptidoglycan isolated from Gram-positive bacteria. To define the physiological function of MKP-1 during Gram-positive bacterial infection, we studied the innate immune responses to Gram-positive bacteria using Mkp-1 knockout (KO) mice. We found that Mkp-1(-/-) macrophages exhibited prolonged activation of p38 and JNK, but not of ERK, following exposure to either peptidoglycan or lipoteichoic acid. Compared with wild-type (WT) macrophages, Mkp-1(-/-) macrophages produced more proinflammatory cytokines such as TNF-alpha and IL-6. Moreover, after challenge with peptidoglycan, lipoteichoic acid, live or heat-killed Staphylococcus aureus bacteria, Mkp-1 KO mice also mounted a more robust production of cytokines and chemokines, including TNF-alpha, IL-6, IL-10, and MIP-1alpha, than did WT mice. Accordingly, Mkp-1 KO mice also exhibited greater NO production, more robust neutrophil infiltration, and more severe organ damage than did WT mice. Surprisingly, WT and Mkp-1 KO mice exhibited no significant difference in either bacterial load or survival rates when infected with live S. aureus. However, in response to challenge with heat-killed S. aureus, Mkp-1 KO mice exhibited a substantially higher mortality rate compared with WT mice. Our studies indicate that MKP-1 plays a critical role in the inflammatory response to Gram-positive bacterial infection. MKP-1 serves to limit the inflammatory reaction by inactivating JNK and p38, thus preventing multiorgan failure caused by exaggerated inflammatory responses.
Wang
Xianxi
X
Center for Perinatal Research, Columbus Children's Research Institute, Columbus Children's Hospital, Columbus, OH 43205, USA.
Meng
Xiaomei
X
Kuhlman
Joshua R
JR
Nelin
Leif D
LD
Nicol
Kathleen K
KK
English
B Keith
BK
Liu
Yusen
Y
D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D002473:Cell Wall / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D054638:Dual Specificity Phosphatase 1; D016908:Gram-Positive Bacterial Infections / Q000276:immunology*; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000502:physiology*; D007249:Inflammation / Q000209:etiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D010457:Peptidoglycan / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000502:physiology*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000502:physiology*; D013203:Staphylococcal Infections / Q000276:immunology / Q000401:mortality; D013682:Teichoic Acids / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018797:Cell Cycle Proteins; D016207:Cytokines; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D013682:Teichoic Acids; C009900:lipoteichoic acid; D009195:Peroxidase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases