Dataset Information

Age-related sensitivity to endotoxin-induced liver inflammation: Implication of inflammasome/IL-1? for steatohepatitis.

ABSTRACT: Aging is associated with increased vulnerability to inflammatory challenge. However, the effects of altered inflammatory response on the metabolic status of tissues or organs are not well documented. In this study, we present evidence demonstrating that lipopolysaccharide (LPS)-induced upregulation of the inflammasome/IL-1? pathway is accompanied with an increased inflammatory response and abnormal lipid accumulation in livers of aged rats. To monitor the effects of aging on LPS-induced inflammation, we administered LPS (2 mg kg(-1) ) to young (6-month old) and aged (24-month old) rats and found abnormal lipid metabolism in only aged rats with increased lipid accumulation in the liver. This lipid accumulation in the liver was due to the dysregulation of PPAR? and SREBP1c. We also observed severe liver inflammation in aged rats as indicated by increased ALT levels in serum and increased Kupffer cells in the liver. Importantly, among many inflammation-associated factors, the aged rat liver showed chronically increased IL-1? production. Increased levels of IL-1? were caused by the upregulation of caspase-1 activity and inflammasome activation. In vitro studies with HepG2 cells demonstrated that treatment with IL-1? significantly induced lipid accumulation in hepatocytes through the regulation of PPAR? and SREBP1c. In summary, we demonstrated that LPS-induced liver inflammation and lipid accumulation were associated with a chronically overactive inflammasome/IL-1? pathway in aged rat livers. Based on the present findings, we propose a mechanism of aging-associated progression of steatohepatitis induced by endotoxin, delineating a pathogenic role of the inflammasome/IL-1? pathway involved in lipid accumulation in the liver.

SUBMITTER: Chung KW

PROVIDER: S-EPMC4531067 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Age-related sensitivity to endotoxin-induced liver inflammation: Implication of inflammasome/IL-1β for steatohepatitis.

Chung Ki Wung KW Lee Eun Kyeong EK Kim Dae Hyun DH An Hye Jin HJ Kim Nam Deuk ND Im Dong Soon DS Lee Jaewon J Yu Byung Pal BP Chung Hae Young HY

Aging cell 20150407 4

Aging is associated with increased vulnerability to inflammatory challenge. However, the effects of altered inflammatory response on the metabolic status of tissues or organs are not well documented. In this study, we present evidence demonstrating that lipopolysaccharide (LPS)-induced upregulation of the inflammasome/IL-1β pathway is accompanied with an increased inflammatory response and abnormal lipid accumulation in livers of aged rats. To monitor the effects of aging on LPS-induced inflamma ...[more]

PMID: 25847140

Similar Datasets

Project description:Interleukin-1β (IL-1β) is one of the most potent pro-inflammatory cytokines implicated in a wide range of autoinflammatory, autoimmune, infectious, and degenerative diseases. Therefore, many researchers have focused on developing therapeutic molecules that inhibit IL-1β-IL-1 receptor 1 (IL-1R1) interaction for the treatment of IL-1-related diseases. Among IL-1-related diseases, osteoarthritis (OA), is characterized by progressive cartilage destruction, chondrocyte inflammation, and extracellular matrix (ECM) degradation. Tannic acid (TA) has been proposed to have multiple beneficial effects, including anti-inflammatory, anti-oxidant, and anti-tumor activities. However, it is unclear whether TA plays a role in anti-IL-1β activity by blocking IL-1β-IL-1R1 interaction in OA. In this study, we report the anti-IL-1β activity of TA in the progression of OA in both in vitro human OA chondrocytes and in vivo rat OA models. Herein, using-ELISA-based screening, natural compound candidates capable of inhibiting the IL-1β-IL-1R1 interaction were identified. Among selected candidates, TA showed hindering IL-1β-IL-1R1 interaction by direct binding to IL-1β using surface plasmon resonance (SPR) assay. In addition, TA inhibited IL-1β bioactivity in HEK-Blue IL-1-dependent reporter cell line. TA also inhibited IL-1β-induced expression of inducible nitric oxide synthase (NOS2), cyclooxygenase-2 (COX-2), IL-6, tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in human OA chondrocytes. Moreover, TA downregulated IL-1β-stimulated matrix metalloproteinase (MMP)3, MMP13, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)4, and ADAMTS5, while upregulating collagen type II (COL2A1) and aggrecan (ACAN). Mechanistically, we confirmed that TA suppressed IL-1β-induced MAPK and NF-κB activation. The protective effects of TA were also observed in a monosodium iodoacetamide (MIA)-induced rat OA model by reducing pain and cartilage degradation and inhibiting IL-1β-mediated inflammation. Collectively, our results provide evidence that TA plays a potential role in OA and IL-1β-related diseases by hindering IL-1β-IL-1R1 interaction and suppressing IL-1β bioactivity.

Project description:Background and aimsThe proinflammatory cytokine IL-1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL-1β promotes liver injury in these diseases is unclear, as no IL-1β receptor-linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy's function in hepatotoxicity from proinflammatory cytokines.Approach and resultsAML12 cells with decreased autophagy from a lentiviral autophagy-related 5 (Atg5) knockdown were resistant to toxicity from TNF, but sensitized to death from IL-1β, which was markedly amplified by TNF co-treatment. IL-1β/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin-1s to prevent death. IL-1β/TNF depleted autophagy-deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL-1β/TNF-induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy-deficient cells. Mice with a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were similarly sensitized to cathepsin-dependent hepatocellular injury and death from IL-1β/TNF in combination, but neither IL-1β nor TNF alone. Knockout mice had increased hepatic inflammation, and IL-1β/TNF-treated, autophagy-deficient AML12 cells secreted exosomes with proinflammatory damage-associated molecular patterns.ConclusionsThe findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL-1β/TNF-induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage-associated molecular patterns.

Dataset Information

Age-related sensitivity to endotoxin-induced liver inflammation: Implication of inflammasome/IL-1? for steatohepatitis.

Publications

Age-related sensitivity to endotoxin-induced liver inflammation: Implication of inflammasome/IL-1β for steatohepatitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets