title: Inhibition of interleukin-10 signaling in lung dendritic cells by toll-like receptor 4 ligands.
abstract: The homeostatic microenvironment in lung is immunosuppressive and interleukin-10 (IL-10) helps maintain this microenvironment. Despite constitutive production of IL-10 in normal lung, macrophages (MØs) and dentritic cells (DCs) remain capable of responding to microorganisms, suggesting that these innate immune cells have a mechanism to override the immunosuppressive effects of IL-10. Prior studies by the authors revealed that Toll-like receptor (TLR) ligands inhibit IL-10 receptor signaling in alveolar macrophages (AMØs), thereby obviating the immunosuppressive activity of IL-10. This report compares the immunologic phenotypes of AMØs and lung DCs and their ability to respond to IL-10 following exposure to microbial stimuli. IL-10 was constitutively produced by normal lung epithelium and exposure to lipopolysaccharide (LPS) in vivo increased the expression of IL-10 during the first 24 hours. AMØs constitutively produced IL-10 mRNA, whereas both AMØs and LDCs constitutively expressed IL-12 mRNA. AMØs and LDCs, as well as bone marrow-derived MØs and DCs, had reduced capacity to activate STAT3 in response to IL-10 if pretreated with LPS. Inhibition was not associated with decreased expression of IL-10 receptor (IL-10R) and was dependent on the MyD88 signaling pathway. These results demonstrate a common underlying regulatory mechanism in both DCs and MØs by which microbial stimuli can override the immunosuppressive effect of constitutive IL-10 production in the lung.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, Kentucky, USA.
authors.forename: Purnima
authors.initials: P
authors.lastname: Jose
authors.forename: Margarita G
authors.initials: MG
authors.lastname: Avdiushko
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Alan M
authors.initials: AM
authors.lastname: Kaplan
authors.forename: Donald A
authors.initials: DA
authors.lastname: Cohen
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000166:cytology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000172:deficiency
chemical_list: D008024:Ligands; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10