title: 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.
abstract: 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.
authors.affiliation: Center for Developmental Pharmacology and Toxicology, Children's Research Institute, Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, Ohio 43205, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhao
authors.forename: Edward G
authors.initials: EG
authors.lastname: Shepherd
authors.forename: Mary E
authors.initials: ME
authors.lastname: Manson
authors.forename: Leif D
authors.initials: LD
authors.lastname: Nelin
authors.forename: Andrey
authors.initials: A
authors.lastname: Sorokin
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000305:Adrenal Cortex Hormones / Q000737:chemistry; D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation; D007700:Kinetics; D008070:Lipopolysaccharides / Q000737:chemistry; D008168:Lung / Q000473:pathology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010749:Phosphoprotein Phosphatases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000305:Adrenal Cortex Hormones; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; 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