Abstract
BackgroundThe ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR) γ plays crucial roles in diverse biological processes including cellular metabolism, differentiation, development, and immune response. However, during IgG immune complex (IgG-IC)-induced acute lung inflammation, its expression and function in the pulmonary tissue remains unknown.ObjectivesThe study is designed to determine the effect of PPARγ on IgG-IC-triggered acute lung inflammation, and the underlying mechanisms, which might provide theoretical basis for therapy of acute lung inflammation.SettingDepartment of Pathogenic Biology and Immunology, Medical School of Southeast UniversitySubjectsMice with down-regulated/up-regulated PPARγ activity or down-regulation of Early growth response protein 1 (Egr-1) expression, and the corresponding controls.InterventionsAcute lung inflammation is induced in the mice by airway deposition of IgG-IC. Activation of PPARγ is achieved by using its agonist Rosiglitazone or adenoviral vectors that could mediate overexpression of PPARγ. PPARγ activity is suppressed by application of its antagonist GW9662 or shRNA. Egr-1 expression is down-regulated by using the gene specific shRNA.Measures and Main ResultsWe find that during IgG-IC-induced acute lung inflammation, PPARγ expression at both RNA and protein levels is repressed, which is consistent with the results obtained from macrophages treated with IgG-IC. Furthermore, both in vivo and in vitro data show that PPARγ activation reduces IgG-IC-mediated pro-inflammatory mediators’ production, thereby alleviating lung injury. In terms of mechanism, we observe that the generation of Egr-1 elicited by IgG-IC is inhibited by PPARγ. As an important transcription factor, Egr-1 transcription is substantially increased by IgG-IC in both in vivo and in vitro studies, leading to augmented protein expression, thus amplifying IgG-IC-triggered expressions of inflammatory factors via association with their promoters.ConclusionDuring IgG-IC-stimulated acute lung inflammation, PPARγ activation can relieve the inflammatory response by suppressing the expression of its downstream target Egr-1 that directly binds to the promoter regions of several inflammation-associated genes. Therefore, regulation of PPARγ-Egr-1-pro-inflammatory mediators axis by PPARγ agonist Rosiglitazone may represent a novel strategy for blockade of acute lung injury.
Highlights
The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR) g plays crucial roles in diverse biological processes including cellular metabolism, differentiation, development, and immune response
We prove that Egr-1 enhances IgG immune complex (IgG-IC)-induced inflammatory response by directly binding to the promoter regions of the pro-inflammatory mediators, and PPARg suppresses inflammation by inhibiting production of Egr-1
We investigate the role of PPARg in IgG-IC-initiated acute lung injury which is reflected by lung permeability, and MPO activity—an indicator of neutrophil accumulation
Summary
The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR) g plays crucial roles in diverse biological processes including cellular metabolism, differentiation, development, and immune response. During IgG immune complex (IgG-IC)-induced acute lung inflammation, its expression and function in the pulmonary tissue remains unknown. The pulmonary diseases, such as acute lung injury (ALI) and its more severe form—acute respiratory distress syndrome (ARDS), are reported to be related with deposition of immune complexes in the tissue [8, 9]. During IgG-IC induction of ALI/ARDS, the local macrophages are firstly activated through engagement of Fcg receptors with the ligands, resulting in the release of numerous cytokines and chemokines. Under the action of the inflammatory factors, alveolar epithelial cells are activated and neutrophils are recruited into the pulmonary tissue. Acute lung injury is triggered by the severe inflammatory response. The molecular events responsible for productions of inflammation-associated mediators are poorly understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
