Liver, Pancreas, and Biliary TractTumor necrosis factor α in the pathogenesis of human and murine fulminant hepatic failure☆,☆☆,★
Section snippets
Patient sera and controls
Twenty-two patients with FHF admitted to our intensive care unit were included in the study. FHF was defined as deterioration of liver function (<14 days) without signs of CLD resulting in jaundice, decrease in coagulation factors (factors V and II <50%), and encephalopathy.22, 23 International normalized ratio, serum transaminase, and bilirubin values were determined as biochemical markers of liver function. Blood was taken from each patient immediately after admission and daily thereafter
Increased serum TNF-α, TNF-R1, and TNF-R2 levels are evident in patients with FHF
Serum samples of patients with FHF showed that levels of TNF-α, sTNF-R1, and sTNF-R2 were significantly increased at all time points compared with controls (P < 0.001 for TNF-α, sTNF-R1, and sTNF-R2; Figure 1.
Discussion
FHF is characterized by the sudden onset of liver deterioration associated with symptoms such as jaundice, encephalopathy, and increased aminotransferase levels. Since the introduction of liver transplantation, the prognosis of patients with FHF has improved.32 However, currently no therapy is available to block liver cell destruction and thus save the organ. Earlier studies indicated that TNF-α production is increased in the serum of FHF patients, but it was unclear how this cytokine might
References (49)
- et al.
Enhanced tumour necrosis factor and interleukin-1 in fulminant hepatic failure
Lancet
(1988) - et al.
The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death
Cell
(1994) - et al.
Pathways leading to cell death in T cells
Curr Opin Immunol
(1997) - et al.
TRADD-TRAF2 and TRADDFADD interactions define two distinct TNF receptor 1 signal transduction pathways
Cell
(1996) - et al.
The TNF receptor 1–associated protein TRADD signals cell death and NF-κB activation
Cell
(1995) - et al.
Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death
Cell
(1996) - et al.
FADD, a novel death domain–containing protein, interacts with the death domain of Fas and initiates apoptosis
Cell
(1995) - et al.
Concanavalin A-induced liver cell damage: activation of intracellular pathways triggered by tumor necrosis factor in mice
Gastroenterology
(1998) - et al.
Tumor necrosis factor receptors in patients with chronic hepatitis B virus infection
Gastroenterology
(1995) - et al.
The designer cytokine hyper-interleukin-6 is a potent activator of STAT3-dependent gene transcription in vivo and in vitro
J Biol Chem
(1999)
Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection
Cell
Concanavalin A-induced T-cell-mediated hepatic injury in mice: the role of tumor necrosis factor
Hepatology
Tumor necrosis factor–induced apoptosis during the poisoning of mice with hepatotoxins
Gastroenterology
Enhanced expression of CD80 (B7-1), CD86 (B7-2), and CD40 and their ligands CD28 and CD154 in fulminant hepatic failure
Am J Pathol
An endotoxin-induced serum factor that causes necrosis of tumors
Proc Natl Acad Sci U S A
Phase I study of recombinant human tumor necrosis factor
Cancer Chemother Pharmacol
A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients
J Clin Oncol
Increased plasma tumor necrosis factor in severe alcoholic hepatitis
Ann Intern Med
The mitochondrial permeability transition is required for tumor necrosis factor alpha–mediated apoptosis and cytochrome c release
Mol Cell Biol
Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kB
Nature
An essential role for NF-κB in preventing TNF-alpha–induced cell death
Science
Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality
Proc Natl Acad Sci U S A
Severe liver degeneration in mice lacking the IκB kinase 2 gene
Science
Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation
Science
Cited by (204)
rhIL-1Ra reduces hepatocellular apoptosis in mice with acute liver failure mainly by inhibiting the activities of Kupffer cells
2019, European Journal of PharmacologyCitation Excerpt :The ratio of serum IL-1Ra and IL-1β levels correlates highly with the final outcome of inflammatory diseases (Dinarello, 2009, 2011; O'Neill, 2008). Kupffer cells (KCs) are macrophages resident in the liver, and they secrete IL-1 and other cytokines that are closely related to ALF (Canbay et al., 2003; Kolios et al., 2006; Streetz et al., 2000; Zhang et al., 2011). A study of ALF rats induced by partial hepatectomy (PH) showed that KCs had been obviously activated after PH, whereas they were essentially normal morphologically in the control (Boermeester et al., 1995).
Diterpenoid trigonoreidon B isolated from Trigonostemon reidioides alleviates inflammation in models of LPS-stimulated murine macrophages and inflammatory liver injury in mice
2018, Biomedicine and PharmacotherapyCitation Excerpt :Proinflammatory cytokines especially tumor necrosis factor-alpha (TNF-α) produced by activated macrophages have been shown to contribute to liver destruction through apoptosis cell death [5]. TNF-α mediates hepatocyte injury via apoptosis induction by binding with its death TNF-α receptor, which leads to caspase activation [6]. Besides cytokines, macrophages also release cytotoxic mediators, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can augment liver damage following exposure to a hepatotoxicant LPS [8,9].
Indoline derivatives mitigate liver damage in a mouse model of acute liver injury
2017, Pharmacological Reports
- ☆
Address requests for reprints to: Christian Trautwein, M.D., Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. e-mail: [email protected]; fax: (49) 511-55-71-03.
- ☆☆
Supported by Deutsche Forschungsgemeinschaft Tr 285 3-4 and the Bonfor program of the University of Bonn.
- ★
This work is dedicated on the occasion of the 70th birthday of Prof. Dr. K.-H. Meyer zum Büschenfelde.