Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha. Role in regulating cell death and pancreatitis.

Gukovskaya, Anna S.; Gukovsky, Ilya; Zaninovic, Vjekoslav; Song, Min Kyung; Sandoval, Darleen A.; Gukovsky, S; Pandol, Stephen J.

doi:10.1172/jci119714

Cited by 348 publications

(315 citation statements)

References 45 publications

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“…This becomes evident when the effects of the inhibitor used in our study are compared in two different organs and models: whereas TNF-␣-and FAS-induced liver apoptosis was significantly decreased (Roquet et al, 1996), the same inhibitor was ineffective in modulating acinar cell apoptosis in acute pancreatitis. Although TNF-␣ is known to be involved in acinar cell apoptosis in acute pancreatitis (Gukovskaya et al, 1997), it did not seem to be the only mechanism involved in the regulation of apoptotic acinar cell death in the current study, because TNF-␣ expression in ICE-I-treated animals was reduced despite the same incidence of apoptosis. Other factors, such as expression and up-regulation of the FAS/FAS ligand system, may outweigh TNF-␣ in this respect (Iovanna, 1996;Roquet et al, 1996).…”

Section: Il-1␤-converting Enzyme In Acute Pancreatitiscontrasting

confidence: 59%

“…The expression of active IL-1␤ and TNF-␣ protein in the pancreata of healthy control animals without any evidence of intrapancreatic leukocyte infiltration and in the absence of detectable mRNA levels strongly suggests that both cytokines are synthesized and stored within the acinar cells themselves and play a physiologic role in the process of tissue homeostasis. So far, this has only been demonstrated for TNF-␣ (Gukovskaya et al, 1997). During the early stages of acute pancreatitis, considerable amounts of intrapancreatic IL-1␤ and TNF-␣ seem to be released by acinar cells undergoing necrosis, which correlates well with the difference in the extent of necrosis found between the treated group and untreated group.…”

Section: Il-1␤-converting Enzyme In Acute Pancreatitismentioning

confidence: 87%

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Differential Effects of Caspase-1/Interleukin-1β–Converting Enzyme on Acinar Cell Necrosis and Apoptosis in Severe Acute Experimental Pancreatitis

Rau

Paszkowski

Lillich

et al. 2001

Laboratory Investigation

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SUMMARY:There is recent experimental evidence that inhibition of caspase-1/interleukin-1␤ converting enzyme (ICE) significantly ameliorates overall severity and survival in severe acute experimental pancreatitis. However, little is known about the effects of this approach on the dynamics and mechanisms of local acinar cell damage, which we aimed to investigate in the present study. Severe acute pancreatitis (SAP) was induced by retrograde infusion of 4% sodium taurocholate in rats treated with isotonic saline or a highly selective, irreversible inhibitor of ICE. After 3, 6, and 24 hours, 3 and 7 days, acinar cell death by necrosis and apoptosis, as well as intrapancreatic and systemic interleukin-1␤ (IL-1␤) and tumor necrosis factor-␣ (TNF-␣) expression, was assessed. Treatment with the ICE inhibitor significantly reduced the extent of acinar cell necrosis accounting for major parenchymal destruction. In contrast, apoptosis was confined to the postacute course of the disease and was closely related to tubular complex formation, both remaining unchanged. Whereas intrapancreatic IL-1␤ mRNA expression was highly up-regulated in both treated and untreated animals, active IL-1␤ protein expression and subsequent neutrophil tissue infiltration was dramatically decreased in the ICE-inhibited group. Parallel to the onset of enhanced apoptotic acinar cell death and tubular complex formation, TNF-␣ mRNA and protein expression was up-regulated, with levels being lower in ICE inhibitor-treated rats. We conclude that activation of caspase-1/ICE plays a central role in the progression of acinar cell death by necrosis in SAP. Herein, IL-1␤-mediated neutrophil infiltration seems to be a crucial step in enhanced cellular destruction. In contrast, acinar cell apoptosis contributes to ductal transformation and is independent of this mechanism, but may be influenced by TNF-␣ (Lab Invest 2001, 81:1001-1013.

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Section: Il-1␤-converting Enzyme In Acute Pancreatitiscontrasting

confidence: 59%

Section: Il-1␤-converting Enzyme In Acute Pancreatitismentioning

confidence: 87%

Differential Effects of Caspase-1/Interleukin-1β–Converting Enzyme on Acinar Cell Necrosis and Apoptosis in Severe Acute Experimental Pancreatitis

Rau

Paszkowski

Lillich

et al. 2001

Laboratory Investigation

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“…Approaches that aim to decrease the systemic inflammatory process and oxidative stress have gained momentum, but a consensus has not yet been formed for a drug that administers effective treatment 6,7,18 .…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effects of ellagic acid on L-arginin ınduced acute pancreatitis

et al. 2016

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PURPOSE:To investigate the therapeutic effects of ellagic acid on L-arginin ınduced acute pancreatitis in rats. METHODS:Thirty-two were split into four groups. Group 1 (control) rats were performed only laparotomy, no drugs were administered. Group 2 (control+EA) rats were administered 85mg/kg EA orally. Rats were sacrificed by cardiac puncture 24 hours after the administration. Group3 (AP) 24 hours after intraperitoneal L-arginine administration, rats were sacrificed by cardiac puncture.Group 4 (EA)-(AP): 85mg/kg EA was administered orally after the L-arginine administration. 24 hours later, rats were sacrificed by cardiac puncture. Serum TNF-α, IL-1β, IL-6, total oxidative status (TOS), total antioxidant capacity (TAC), amylase levels were determined in all groups. RESULTS:Group 3 (AP) rats showed significantly raised TOS level as compared to Group1 (control) rats (p<0.001). Following the EA therapy, a decrease in TOS was observed in Group 4 (AP+EA). TAC levels were significantly raised in the Group 4 (AP+EA) compared to the Group 3 (AP) (p=0.003). Group 3 (AP) showed significantly increased TNF-α, IL-1β and IL-6 serum levels as compared to Group 4 (AP+EA). Histopathological changes were supported our result. CONCLUSION:The healing effects of ellagic acid on inflammatory and oxidative stress were confirmed by histopathological and biochemical evaluations of the pancreatic tissue.

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“…49,50 To elucidate whether bilirubin cytotoxicity is due to induction of cellular necrosis, release of LDH from bilirubin-treated HCT15 cells was assessed at 24 and 48 hr. For these studies, HCT15 monolayers were incubated in the presence of bilirubin (50 M) or DMSO vehicle, and the concentration of FIGURE 3 -LDH release from colon cancer cells treated with bilirubin.…”

Section: Mechanism Of Bilirubin-induced Cell Deathmentioning

confidence: 99%

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

Keshavan¹,

Schwemberger²,

Smith³

et al. 2004

Intl Journal of Cancer

112

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Bilirubin is the principal end product of heme degradation. Prompted by epidemiologic analyses demonstrating an inverse correlation between serum bilirubin levels and cancer mortality, we examined the effect(s) of bilirubin on the growth and survival of colon adenocarcinoma cells. Adenocarcinoma cell monolayers were treated with bilirubin over a range of bilirubin:BSA molar ratios (0 -0.6), and viability was assessed colorimetrically. Apoptosis was characterized by TUNEL assay, annexin V staining and caspase-3 activation. The mechanism(s) by which bilirubin induces apoptosis was investigated by Western blotting for cytochrome c release, assaying for caspase-8 and caspase-9 activation and for mitochondrial depolarization by JC-1 staining. The direct effect of bilirubin on the membrane potential of isolated mitochondria was evaluated using light-scattering and fluorescence techniques. Bilirubin decreased the viability of all colon cancer cell lines tested in a dose-dependent manner. Cells exhibited substantial apoptosis when exposed to bilirubin concentrations ranging 0 -50 M, as demonstrated by an 8-to 10-fold increase in TUNEL and annexin V staining and in caspase-3 activity. Bilirubin treatment evokes specific activation of caspase-9, enhances cytochrome c release into the cytoplasm and triggers the mitochondrial permeability transition in colon cancer monolayers. Additionally, bilirubin directly induces the depolarization of isolated rat liver mitochondria, an effect that is not inhibited by cyclosporin A. Bilirubin stimulates apoptosis of colon adenocarcinoma cells in vitro through activation of the mitochondrial pathway, apparently by directly dissipating mitochondrial membrane potential. As this effect is triggered at concentrations normally present in the intestinal lumen, we postulate a physiologic role for bilirubin in modulating colon tumorigenesis.

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Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha. Role in regulating cell death and pancreatitis.

Abstract: The aim of this study was to determine whether tumor necrosis factor-␣ (TNF ␣ )

Cited by 348 publications

References 45 publications

Differential Effects of Caspase-1/Interleukin-1β–Converting Enzyme on Acinar Cell Necrosis and Apoptosis in Severe Acute Experimental Pancreatitis

Differential Effects of Caspase-1/Interleukin-1β–Converting Enzyme on Acinar Cell Necrosis and Apoptosis in Severe Acute Experimental Pancreatitis

Therapeutic effects of ellagic acid on L-arginin ınduced acute pancreatitis

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

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