TY - JOUR
TI - MAP3K8 regulates cox-2-mediated prostaglandin E2 production in the lung and suppresses pulmonary inflammation and fibrosis
AU - Zannikou, M.
AU - Barbayianni, I.
AU - Fanidis, D.
AU - Grigorakaki, T.
AU - Vlachopoulou, E.
AU - Konstantopoulos, D.
AU - Fousteri, M.
AU - Nikitopoulou, I.
AU - Kotanidou, A.
AU - Kaffe, E.
AU - Aidinis, V.
JO - Journal of Immunological Methods
PY - 2021
VL - 206
TODO - 3
SP - 607-620
PB - American Association of Immunologists
SN - 0022-1759
TODO - 10.4049/jimmunol.2000862
TODO - bleomycin;  cyclooxygenase 2;  messenger RNA;  mitogen activated protein kinase kinase kinase;  mitogen activated protein kinase kinase kinase 8;  prostaglandin E2;  unclassified drug;  cyclooxygenase 2;  MAP3K8 protein, human;  mitogen activated protein kinase kinase kinase;  oncoprotein;  prostaglandin E2, animal experiment;  animal model;  animal tissue;  Article;  controlled study;  disease exacerbation;  enzyme regulation;  enzyme synthesis;  female;  fibrosing alveolitis;  gene deletion;  hematopoietic cell;  in vivo study;  macrophage;  male;  microarray analysis;  mouse;  nonhuman;  pathogenesis;  priority journal;  protein expression;  protein homeostasis;  protein protein interaction;  protein RNA binding;  animal;  bone marrow transplantation;  C57BL mouse;  cell culture;  fibrosis;  genetics;  human;  immunosuppressive treatment;  inflammation;  knockout mouse;  lung;  lung fibrosis;  metabolism;  pathology, Animals;  Bone Marrow Transplantation;  Cells, Cultured;  Cyclooxygenase 2;  Dinoprostone;  Fibrosis;  Humans;  Immunosuppression;  Inflammation;  Lung;  MAP Kinase Kinase Kinases;  Mice;  Mice, Inbred C57BL;  Mice, Knockout;  Proto-Oncogene Proteins;  Pulmonary Fibrosis
TODO - Idiopathic pulmonary fibrosis (IPF) is characterized by exuberant deposition of extracellular matrix components, leading to the deterioration of lung architecture and respiratory functions. Profibrotic mechanisms are controlled by multiple regulatory molecules, including MAPKs, in turn regulated by multiple phosphorylation cascades. MAP3K8 is an MAPK kinase kinase suggested to pleiotropically regulate multiple pathogenic pathways in the context of inflammation and cancer; however, a possible role in the pathogenesis of IPF has not been investigated. In this report, MAP3K8 mRNA levels were found decreased in the lungs of IPF patients and of mice upon bleomycin-induced pulmonary fibrosis. Ubiquitous genetic deletion of Map3k8 in mice exacerbated the modeled disease, whereas bone marrow transfer experiments indicated that although MAP3K8 regulatory functions are active in both hematopoietic and nonhematopoietic cells, Map3k8 in hematopoietic cells has a more dominant role. Macrophage-specific deletion of Map3k8 was further found to be sufficient for disease exacerbation thus confirming a major role for macrophages in pulmonary fibrotic responses and suggesting a main role for Map3k8 in the homeostasis of their effector functions in the lung. Map3k8 deficiency was further shown to be associated with decreased Cox-2 expression, followed by a decrease in PGE2 production in the lung; accordingly, exogenous administration of PGE2 reduced inflammation and reversed the exacerbated fibrotic profile of Map3k8 2/2 mice. Therefore, MAP3K8 has a central role in the regulation of inflammatory responses and Cox-2-mediated PGE2 production in the lung, and the attenuation of its expression is integral to pulmonary fibrosis development. Copyright © 2021 by The American Association of Immunologists, Inc.
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