Cytokine-Induced Inflammatory Liver Injuries

Tsutsui, Hiroko; Adachi, Keishi; Seki, Eiichiro; Nakanishi, Kenji

doi:10.2174/1566524033479618

Cited by 54 publications

(54 citation statements)

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“…It is possible that MyD88 signaling in the regenerating liver depends on IL-1 and IL-18 rather than LPS. However, a number of experiments in hepatocyte cultures suggest that IL-1␤ inhibits hepatocyte replication (41,42), while IL-18 expression has been associated with liver injury rather than cell proliferation (43,44). IL-18 is also known as IFN-␥-inducing factor, and recently we and others have demonstrated that IFN-␥ inhibits hepatocyte proliferation and liver regeneration (45,46).…”

Section: Discussionmentioning

confidence: 98%

Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4

Campbell¹,

Riehle

Brooling³

et al. 2006

The Journal of Immunology

101

121

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TNF and IL-6 are considered to be important to the initiation or priming phase of liver regeneration. However, the signaling pathways that lead to the production of these cytokines after partial hepatectomy (PH) have not been identified. Enteric-derived LPS appears to be important to liver regeneration, possibly by stimulating proinflammatory cytokine production after surgery. To determine whether LPS signaling pathways are involved in the regulation of the proinflammatory cytokines TNF and IL-6 during the priming phase of liver regeneration, we performed PH on mice lacking the TLRs Tlr4 and Tlr2, the LPS coreceptor, Cd14, and Myd88, an adapter protein involved in most TLR and IL-1R pathways. In MyD88 knockout (KO) mice after PH, both liver Tnf mRNA and circulating IL-6 levels were severely depressed compared with heterozygous or wild-type mice. Activation of STAT-3 and three STAT-3 responsive genes, Socs3, Cd14, and serum amyloid A2 were also blocked. In contrast, Tlr4, Tlr2, and Cd14 KO mice showed no deficits in the production of IL-6. Surprisingly, none of these KO mice showed any delay in hepatocyte replication. These data indicate that the LPS receptor TLR4, as well as TLR2 and CD14, do not play roles in regulating cytokine production or DNA replication after PH. In contrast, MyD88-dependent pathways appear to be responsible for TNF, IL-6, and their downstream signaling pathways.

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Section: Discussionmentioning

confidence: 98%

Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4

Campbell¹,

Riehle

Brooling³

et al. 2006

The Journal of Immunology

101

121

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“…These procytokines are cleaved by caspase-1 activated by the NLRP3 inflammasome. In turn, mature IL-1b and IL-18 upregulate innate immune responses in local immune cells (23,33). Specifically, Kupffer cells (the resident macrophages of the liver) can propagate the hepatic innate inflammatory response through the production of proinflammatory TNF-␣ (19,20).…”

Section: Discussionmentioning

confidence: 99%

P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice

Hoque

Sohail

Salhanick

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

127

111

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SC, Mehal WZ. P2x7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice. Am J Physiol Gastrointest Liver Physiol 302: G1171-G1179, 2012. First published March 1, 2012; doi:10.1152/ajpgi.00352.2011.-Inflammation contributes to liver injury in acetaminophen (APAP) hepatotoxicity in mice and is triggered by stimulation of immune cells. The purinergic receptor P2X7 is upstream of the nod-like receptor family, pryin domain containing-3 (NLRP3) inflammasome in immune cells and is activated by ATP and NAD that serve as damage-associated molecular patterns. APAP hepatotoxicity was assessed in mice genetically deficient in P2X7, the key inflammatory receptor for nucleotides (P2X7Ϫ/Ϫ), and in wild-type mice. P2X7Ϫ/Ϫ mice had significantly decreased APAP-induced liver necrosis. In addition, APAP-poisoned mice were treated with the specific P2X7 antagonist A438079 or etheno-NAD, a competitive antagonist of NAD. Pre-or posttreatment with A438079 significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury in wild-type but not P2X7Ϫ/Ϫ mice. Pretreatment with etheno-NAD also significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury. In addition, APAP toxicity in mice lacking the plasma membrane ectoNTPDase CD39 (CD39Ϫ/Ϫ) that metabolizes ATP was examined in parallel with the use of soluble apyrase to deplete extracellular ATP in wild-type mice. CD39Ϫ/Ϫ mice had increased APAP-induced hemorrhage and mortality, whereas apyrase also decreased APAP-induced mortality. Kupffer cells were treated with extracellular ATP to assess P2X7-dependent inflammasome activation. P2X7 was required for ATP-stimulated IL-1␤ release. In conclusion, P2X7 and exposure to the ligands ATP and NAD are required for manifestations of APAPinduced hepatotoxicity.CD39; nod-like receptor family, pryin domain containing-3, caspase-1; inflammasome; damage-associated molecular pattern ACETAMINOPHEN (APAP) overdose is the most common cause of acute liver failure in the Unites States and Europe (15,18,24). Furthermore, cases of acute hepatic failure due to APAP continue to rise (24). Toxicity is initiated by metabolism of APAP via reductive pathways to reactive metabolites. An antidote exists for patients early in the course of poisoning during this metabolism phase. However, with increased delays in administration of therapy, the frequency with which patients develop hepatocellular injury worsens.The initial, direct toxic injury induces an area of necrosis in the centrilobular regions. Liver injury is propagated by an inflammatory response after the drug has been metabolized and the initial centrilobular injury has occurred (23). The nature of this inflammatory response has been the subject of significant investigation in the past several years.Prior research by our group indicates that inflammasome activation is a crucial initiating step in the propagation of APAP-induced hepatic injury (10). Proinflammatory cytokines IL-1␤ and IL-18 are thought to be crucial to the prop...

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“…Lck is an attractive target to block T cell activation for a number of reasons (Tsutsui et al, 2003). First, Lck is crucial in the activation of T cells causing clonal expansion and generation of a cytotoxic T cell response (Weiss and Littman, 1994).…”

Section: Discussionmentioning

confidence: 99%

A-770041, a Novel and Selective Small-Molecule Inhibitor of Lck, Prevents Heart Allograft Rejection

Stachlewitz

Hart²,

Bettencourt³

et al. 2005

J Pharmacol Exp Ther

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Lck, one of eight members of the Src family of tyrosine kinases, is activated after T cell stimulation and is required for T-cell proliferation and interleukin (IL)-2 production. Inhibition of Lck has been a target to prevent lymphocyte activation and acute rejection. Here, we report the pharmacologic characterization of 1-methyl-1H-indole-2-carboxylic acid, an orally bioavailable pyrazolo [3,4-d]pyrimidine with increased selectivity for Lck compared with previously reported compounds.

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Cytokine-Induced Inflammatory Liver Injuries

Cited by 54 publications

References 0 publications

Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4

Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4

P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice

A-770041, a Novel and Selective Small-Molecule Inhibitor of Lck, Prevents Heart Allograft Rejection

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