The inhibitory action of PDCD4 in lipopolysaccharide/D-galactosamine-induced acute liver injury

Abstract

Programmed cell death 4 (PDCD4) acts as a tumor suppressor gene, which suppresses tumor growth, infiltration and metastasis. Our previous studies demonstrated that PDCD4 had an important role in the development of ovarian cancer and glioma. Recent studies show that PDCD4 is also involved in various inflammatory diseases. However, its exact effect on inflammation remains unclear. In our current study, we explored the role of PDCD4 in acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) using wild-type (WT) mice and PDCD4-deficient mice. Our results showed that liver-to-body weight ratios, as well as serum aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly increased in PDCD4-deficient mice than WT mice. Histological examination, immunohistochemical and TUNEL analysis revealed PDCD4-deficient mice had more necrotic and apoptotic hepatocytes, inflammatory cells infiltration and liver internal hemorrhage than WT mice. In addition, some inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) in the serum and liver tissues were also significantly increased in PDCD4-deficient mice. More importantly, we found that the aggravation of liver tissue injury in PDCD4-deficient mice was due to excessive mitogen-activated protein kinase and NF-kB activation, which induced the release of more inflammatory factors, and consequently resulted in higher levels of hepatocyte necrosis and apoptosis. These results indicate that PDCD4 has a protective role in LPS/D-GalN-induced acute liver injury. This finding may present new opportunities for PDCD4 to be explored as a therapeutic target in acute liver injury.

Asiatic Acid Exhibits Anti-inflammatory and Antioxidant Activities against Lipopolysaccharide and d-Galactosamine-Induced Fulminant Hepatic Failure

“…Wang et al (26) discovered that PDCD4 deficiency aggravated colitis via promoting the IL-6/STAT3 pathway in mice. However, Schmid et al (27) maintained that inflammation could induce the loss of PDCD4, and Wang et al (8) indicated that PDCD4 upregulation inhibited inflammatory responses by inhibiting NF-κB and MAPK signaling pathway activation in an LPS/ d -GalN-induced mouse model. Therefore, PDCD4 may be closely associated with inflammatory responses.…”

“…Our results showed that AA treatment effectively inhibited L/D-induced JNK, ERK, P38, P65, and IκBα phosphorylation and blocked IκBα degradation. Moreover, PDCD4 downregulation was reported to promote LPS-stimulated secretion of proinflammatory mediators, and PDCD4 deficiency exacerbated the sensitivity of liver injury in L/D-induced mice by inducing MAPK and NF-κB pathway activation (8, 43). Our studies revealed that L/D exposure dramatically decreased PDCD4 protein expression, whereas this effect was significantly suppressed by AA pretreatment.…”

“…Importantly, the tumor suppressor programmed cell death-4 (PDCD4) gene, which was initially regarded as an upregulated gene during apoptosis, is universally expressed in normal tissues, with the highest levels found in the liver (7). Additionally, PDCD4 can mediate inflammatory responses that play essential roles in the amelioration of LPS/ d -GalN-induced acute liver injury via inhibition of MAPK and NF-κB pathway activation (8). More intriguingly, apart from inflammatory responses, the excessive accumulation of reactive oxygen species (ROS) is recognized to a possible mechanism of d -GalN/LPS-induced FHF (9).…”

Andrographolide ameliorates d-galactosamine/lipopolysaccharide-induced acute liver injury by activating Nrf2 signaling pathway

“…Elevated inflammatory cytokine productions were observed in mice of LPS/GalN-induced liver injury [17]. These inflammatory cytokines, especially TNF-α and IL-1β, have been known to play critical roles in the pathogenesis of liver injury [18, 19].…”

Role of PDCD4 in inflammation and tumors: a double-edged sword

“…了肝细胞的凋亡和坏死, 在血清和肝组织中提高了IL-6, MCP-1, TNF-α, IL-1β等多种促炎性细胞因子的表达 水平 [76] . [74,75] ; 在高脂诱导的肥胖模型中, PDCD4主要是通过调控巨噬细胞极化和脂质代谢发 挥作用 [48] ; 在LPS诱导急性肝损伤模型和DSS诱导的 急性结肠炎模型中, PDCD4主要通过调节巨噬细胞的 功能发挥作用 [68,76] . 另有报道 [77] , IFN-α可通过p70 S6…”