The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharide: attenuation of proinflammatory cytokine biosynthesis via feedback control of p38. J Biol Chem 2005 Mar 04;280(9):8101-8
Date
12/14/2004Pubmed ID
15590669DOI
10.1074/jbc.M411760200Scopus ID
2-s2.0-14844310210 (requires institutional sign-in at Scopus site) 194 CitationsAbstract
Mitogen-activated protein (MAP) kinases are critical mediators of innate immune responses. In response to lipopolysaccharide (LPS), MAP kinases are rapidly activated and play an important role in the production of proinflammatory cytokines. Although a number of MAP kinase phosphatases (MKPs) have been identified, their roles in the control of cytokine production have not been well defined. In the present report, we investigated the role of MKP-1 in alveolar macrophages stimulated with LPS. We found that LPS triggered transient activation of three MAP kinase subfamilies, ERK, JNK, and p38, in both immortalized and primary murine alveolar macrophages. MKP-1 was rapidly induced by LPS, and its induction correlated with the dephosphorylation of these MAP kinases. Blocking MKP-1 with triptolide prolonged the activities of both JNK and p38 in immortalized alveolar macrophages. Stimulation of primary alveolar macrophages isolated from MKP-1-deficient mice with LPS resulted in a prolonged p38 phosphorylation compared with wild type alveolar macrophages. Accordingly, these MKP-1-deficient alveolar macrophages also mounted a more robust and rapid tumor necrosis factor alpha production than their wild type counterparts. Adenovirus-mediated MKP-1 overexpression significantly attenuated tumor necrosis factor alpha production in immortalized alveolar macrophages. Finally, MKP-1 was induced by a group of corticosteroids frequently prescribed for the treatment of inflammatory lung diseases, and the anti-inflammatory potencies of these drugs closely correlated with their abilities to induce MKP-1. Our studies indicated that MKP-1 plays an important role in dampening the inflammatory responses of alveolar macrophages. We speculate that MKP-1 may represent a novel target for therapeutic intervention of inflammatory lung diseases.
Author List
Zhao Q, Shepherd EG, Manson ME, Nelin LD, Sorokin A, Liu YAuthor
Andrey Sorokin PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenoviridaeAdrenal Cortex Hormones
Animals
Blotting, Northern
Blotting, Southern
Blotting, Western
Cell Cycle Proteins
Cell Line
Cells, Cultured
Dual Specificity Phosphatase 1
Enzyme Activation
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation
Green Fluorescent Proteins
Immediate-Early Proteins
Inflammation
Kinetics
Lipopolysaccharides
Lung
MAP Kinase Signaling System
Macrophages
Macrophages, Alveolar
Male
Mice
Mice, Inbred C57BL
Microscopy, Fluorescence
Phosphoprotein Phosphatases
Phosphorylation
Protein Phosphatase 1
Protein Tyrosine Phosphatases
RNA, Messenger
Time Factors
p38 Mitogen-Activated Protein Kinases
