CCAAT/Enhancer-Binding Protein δ Is a Critical Mediator of Lipopolysaccharide-Induced Acute Lung Injury

Abstract

Although inflammation plays a central role in the pathogenesis of acute lung injury, the molecular mechanisms underlying inflammatory responses in acute lung injury are poorly understood, and therapeutic options remain limited. CCAAT/enhancer-binding proteins, C/EBPβ and C/EBPδ, are expressed in the lung and have been implicated in the regulation of inflammatory mediators. However, their functions in lung pathobiological characteristics are not well characterized. Herein, we show that C/EBPβ and C/EBPδ are activated in mouse lung after intrapulmonary deposition of lipopolysaccharide (LPS). Mice carrying a targeted deletion of the C/EBPδ gene displayed significant attenuation of the lung permeability index (lung vascular leak of albumin), lung neutrophil accumulation (myeloperoxidase activity), and neutrophils in bronchial alveolar lavage fluids compared with wild-type mice. These phenotypes were consistent with morphological evaluation of lung, which showed reduced inflammatory cell influx and minimal intra-alveolar hemorrhage. Moreover, mutant mice expressed considerably less tumor necrosis factor-α, IL-6, and macrophage inflammatory protein-2 in bronchial alveolar lavage fluids in LPS-injured lung compared with wild-type mice. In contrast, C/EBPβ deficiency had no effect on LPS-induced lung injury. By using small-interfering RNA-mediated knockdown for C/EBPδ, we demonstrate, for the first time to our knowledge, that C/EBPδ plays a critical role for the tumor necrosis factor-α, IL-6, and macrophage inflammatory protein-2 production in LPS-stimulated alveolar macrophages. These findings demonstrate that C/EBPδ, but not C/EBPβ, plays an important role in LPS-induced lung inflammatory responses and injury.

C/EBPβ and C/EBPδ transcription factors: Basic biology and roles in the CNS

“…Based on this and other studies, C/EBPδ has been categorized as a LPS-induced secondary response gene in macrophages whereas C/EBPβ would belong to a third wave of transcription factor activation (Medzhitov and Horng 2009). The best described role for C/EBPδ activation in macrophages is the M a n u s c r i p t promotion of pro-inflammatory gene transcription Litvak et al 2009;Yan et al 2013), although a recent study suggests an effect of C/EBPδ on macrophage migration/mobilization rather than on pro-inflammatory expression (Duitman et al 2012). Regulation of anti-inflammatory gene expression has not been well established.…”

CCAAT-enhancer binding protein delta (C/EBPδ) attenuates tubular injury and tubulointerstitial fibrogenesis during chronic obstructive nephropathy

“…24 Moreover, C/EBPd modulates the expression of CCL20, interleukin (IL)-23, CXCL1, and TNFAIP6 in macrophages, and these C/EBPd targets subsequently potentiate the pathogenesis of rheumatoid arthritis, 25 whereas macrophage C/EBPd also induces phagocytosis of apoptotic neuronal cells. 26 Finally, a recent paper shows that C/EBPd directly drives LPS-induced tumor necrosis factor-a, IL-6, and macrophage inflammatory protein-2 in pulmonary macrophages, 27 which may be due to C/EBPd-dependent tolllike receptor-4 expression. 28 Interestingly, C/EBPd also modifies renal inflammation, as C/EBPd deficiency protected against Habu snake venom-induced glomerulonephritis.…”

Transcriptional Regulation of the Group IIA Secretory Phospholipase A2 Gene by C/EBPδ in Rat liver and its Relationship to Hepatic luconeogenesis during Sepsis

“…C/EBPδ is a member of the C/EBP family of transcription factors and it has been implicated to play an important role in the inflammatory responses such as sepsis and endotoxemia [22,23,36]. C/EBPδ mRNA and protein are expressed in normal tissues at a low level but are rapidly and drastically induced in many tissues by bacterial lipopolysaccharide or numerous proinflammatory mediators [21-23,36-40].…”

“…Element C contains CCAAT/enhancer binding protein δ) (C/EBPδ) binding sites with high affinity [19]. Since C/EBPδ has been reported to function as a positive regulator for sPLA 2 gene transcription [19,20] and the C/EBPδ isoform expression has been reported to increase in multiple tissues following endotoxin administration [21-23], the present study was undertaken to test our hypothesis that the altered transcription of sPLA 2 gene is regulated by C/EBPδ in the liver, and to assess its relationship to hepatic glucose homeostasis, during the progression of sepsis. A network figure of regulation signalling pathway of factors mentioned above was illustrated in Figure 1.…”