Critical role for CCAAT/enhancer-binding protein β in immune complex-induced acute lung injury.
C/EBPs, particularly C/EBPβ and C/EBPδ, are known to participate in the regulation of many genes associated with inflammation. However, very little is known regarding the activation and functions of C/EBPβ and C/EBPδ in acute lung inflammation and injury. In this study, we show that both C/EBPβ and C/EBPδ activation are triggered in lungs and in alveolar macrophages following intrapulmonary deposition of IgG immune complexes. We further show that mice carrying a targeted deletion of the C/EBPβ gene displayed significant attenuation of the permeability index (lung vascular leak of albumin), lung neutrophil accumulation (myeloperoxidase activity), total number of WBCs, and neutrophils in bronchoalveolar lavage fluids compared with wild-type mice. Moreover, the mutant mice expressed considerably less TNF-α, IL-6, and CXC/CC chemokine and soluble ICAM-1 proteins in bronchoalveolar lavage fluids, and corresponding mRNAs in the IgG immune complex-injured lung, compared with wild-type mice. These phenotypes were associated with a significant reduction in morphological lung injury. In contrast, C/EBPδ deficiency had no effect on IgG immune complex-induced lung injury. IgG immune complex-stimulated C/EBPβ-deficient alveolar macrophages released significantly less TNF-α, IL-6, MIP-2, keratinocyte cell-derived chemokine, and MIP-1α compared with wild-type cells. Similar decreases in IgG immune complex-induced inflammatory mediator production were observed following small interfering RNA ablation of C/EBPβ in a murine alveolar macrophage cell line. These findings implicate C/EBPβ as a critical regulator of IgG immune complex-induced inflammatory responses and injury in the lung.
Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chunguang
C
Yan
Min
M
Wu
Jay
J
Cao
Huifang
H
Tang
Mei
M
Zhu
Peter F
PF
Johnson
Hongwei
H
Gao
D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000936:Antigen-Antibody Complex / Q000008:administration & dosage* / Q000009:adverse effects; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000009:adverse effects; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000009:adverse effects / Q000502:physiology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D000936:Antigen-Antibody Complex; D022782:CCAAT-Enhancer-Binding Protein-beta; C497253:Cebpd protein, mouse; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D051743:CCAAT-Enhancer-Binding Protein-delta