Activation of pancreatic acinar cells on isolation from tissue: cytokine upregulation via p38 MAP kinase

Blinman, Thane A.; Gukovsky, Ilya; Mouria, Michelle; Zaninovic, Vjekoslav; Livingston, Edward H.; Pandol, Stephen J.; Gukovskaya, Anna S.

doi:10.1152/ajpcell.2000.279.6.c1993

Cited by 128 publications

(101 citation statements)

References 41 publications

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“…However, it remains unclear which cells are secreting IL-6 in the pancreas. Recently, pancreatic acinar cells isolated from rodent were shown to express IL-6 (33). To the best of our knowledge, this study is the first report to demonstrate one of the local biosynthetic sites for IL-6 in human pancreas.…”

Section: Discussionmentioning

confidence: 55%

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IL-6 Secretion by Human Pancreatic Periacinar Myofibroblasts in Response to Inflammatory Mediators

Shimada

Andoh

Hata

et al. 2002

The Journal of Immunology

131

116

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There is increasing evidence that IL-6 plays an important role in the pathophysiology of acute pancreatitis via its broad proinflammatory actions. To identify the local biosynthetic site for IL-6 in human pancreas, we investigated IL-6 secretion in human pancreatic periacinar myofibroblasts. IL-6 secretion was determined by ELISA and Northern blotting. The activation of NF-κB was assessed by EMSA. The activation of mitogen-activated protein kinase (MAPK) was assessed by immunoblotting. IL-6 secretion was rapidly induced by IL-17, IL-1β, and TNF-α. EMSAs demonstrated that IL-17, IL-1β, and TNF-α induced NF-κB activation within 1.5 h after stimulation, and a blockade of NF-κB activation by the pyrrolidine derivative of dithiocarbamate and tosyl-phe-chloromethylketone markedly reduced the IL-17-, IL-1β-, or TNF-α-induced IL-6 gene expression. Furthermore, IL-17, IL-1β, and TNF-α induced a rapid activation of extracellular signal-related kinase p42/44 and p38 MAPKs, and specific MAPK inhibitors (SB203580, PD98059, and U0216) significantly reduced IL-17-, IL-1β-, or TNF-α-induced IL-6 secretion, indicating the role of MAPKs in the induction of IL-6. The combination of either IL-17 plus IL-1β or IL-17 plus TNF-α enhanced IL-6 secretion and IL-6 mRNA expression; in particular, the effects of IL-17 plus TNF-α were much stronger than those induced by IL-17 plus IL-1β. TNF-α-induced IL-6 mRNA degraded rapidly at any concentrations, and the combination of IL-17 and TNF-α markedly enhanced IL-6 mRNA stability. This indicates that the effects of IL-17 plus TNF-α were regulated at the post-transcriptional level. In conclusion, pancreatic periacinar myofibroblasts secreted a large amount of IL-6 in response to proinflammatory cytokines. These cells might play an important role in the pathogenesis of acute pancreatitis via IL-6 secretion.

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Section: Discussionmentioning

confidence: 55%

“…In various cells, the MAPK family has been shown to play an important role in regulating gene expression in response to inflammatory mediators (33). However, it has not fully been studied whether MAPKs participate in IL-17 signaling.…”

Section: Il-17 Il-1␤ and Tnf-␣ Induce The Activation Of Mapksmentioning

confidence: 99%

IL-6 Secretion by Human Pancreatic Periacinar Myofibroblasts in Response to Inflammatory Mediators

Shimada

Andoh

Hata

et al. 2002

The Journal of Immunology

131

116

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“…An in-vitro experiment showed that cytokine expression of acinar cells was mediated by two separate signal pathways, i.e, NF-κB and p38 MAP kinase. of which p38 MAP kinase is now suggested to play a major role [22][23][24][25][26][27] . The definitive role of these intracellular signaling cascades may lead to new designs for cytokine modulation therapy.…”

Section: Introductionmentioning

confidence: 99%

Effect of NF-κB and p38 MAPK in activated monocytes/macrophages on pro-inflammatory cytokines of rats with acute pancreatitis

Liu¹,

Pan²,

Liu³

et al. 2003

WJG

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AIM: Proinflammatory cytokines TNF-α and IL-6 play a main role in acute pancreatitis (AP). Cytokine biosynthesis runs through two major signaling pathways at the level of proteins: nuclear transcription factor-κB (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK). The aim of the study was to investigate the effect of NF-κB and p38 MAPK in activated monocytes/macrophages on cytokines of rats with acute pancreastitis. METHODS:Taurocholate (3 % and 5 %) at doses of 1 mL/kg was administered into the biliopancreatic duct of male Sprague-Dawley (SD) rats to reduce acute edematous pancreariris (AEP) and acute necrotizing pancreatitis (ANP). Pancreatic tissues were prepared immediately after death. At this point, blood was obtained for determination of serum amylase and pro-inflammatory TNF-α and IL-6. Activated monocytes/macrophages were captured from blood and so were ascites. NF-κB and p38 MAPK in activated monocytes/ macrophages were measured by immunohistochemistry method. Pancreatic tissue samples were prepared for routine light microscopy, using hematoxylin and eosin (HE) staining. RESULTS:The serum levels of amylase were 3 056.00± 1 232.35 IU/L and 4 865.12±890.34 IU/L at 3 and 6 hours in ANP group, which were significantly higher than those (3 056.00±1 232.35 IU/L and 3 187.17±821.16 IU/L) (P<0.05, respectively) in AEP group. In ascites the levels were 3.32±1.01 g and 3.76±1.12 g at 3 and 6 hours in ANP group, which were significantly higher than those (1.43±1.02 g and 2.56±1.21 g) (P<0.05, respectively) in AEP group. The serum levels of TNF-α were 54.27±23.48 pg/ml and 67.83±22.02 pg/ml in AEP group and 64.28±20.79 pg/ml and 106.59± 43.71 pg/ml in ANP group, and the serum levels of IL-6 were 428.12±140.30 pg/ml and 420.13±139.40 pg/ml in AEP group and 1 600.32±309.78 pg/ml and 2 203.76±640.85 pg/ml in ANP group, which were far significantly higher than those in sham group (P<0.001, respectively). The serum level of TNF-α 6 hours after establishment of the studied model and that of IL-6 at 3 and 6 hours in ANP group were significantly higher than those in AEP (P<0. 05, P<0.001, P<0.05). In ANP group, the levels of serum TNF-α and IL-6 6 hours after establishment of the studied model were significantly higher than those 3 hours after establishment of studied model (P<0.05, P<0.05, respectively). Three and 6 hours after establishment of the model, typical pathological changes of AEP and ANP were found,

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“…Although the cascade of events during pancreatic cell isolation that may cause ␤-cell dysfunction and death is not fully characterized, recent lines of research in rodents (11,12) and humans (13) have indicated that oxidative stress plays a major role in triggering the death of islets and surrounding exocrine tissue. Other reports have demonstrated that oxidative stress is strongly connected to the adverse effects of chronic hyperglycemia on insulin biosynthesis by islet ␤-cells (14 -16).…”

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confidence: 99%

Response of Human Islets to Isolation Stress and the Effect of Antioxidant Treatment

et al. 2004

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The process of human islet isolation triggers a cascade of stressful events in the islets of Langerhans involving activation of apoptosis and necrosis and the production of proinflammatory molecules that negatively influence islet yield and function and may produce detrimental effects after islet transplantation. In this study, we showed that activation of nuclear factor-B (NF-B) and poly(ADP-ribose) polymerase (PARP), two of the major pathways responsible for cellular responses to stress, already occurs in pancreatic cells during the isolation procedure. NF-B؊dependent reactions, such as production and release of interleukin-6 and -8 and macrophage chemoattractant protein 1, were observed days after the isolation procedure in isolated purified islets. Under culture conditions specially designed to mimic isolation stress, islet proinflammatory responses were even more pronounced and correlated with higher islet cell loss and impaired secretory function. Here we present novel evidence that early interventions aimed at reducing oxidative stress of pancreatic cells and islets through the use of the catalytic antioxidant probe AEOL10150 (manganese [III] 5,10,15,20-tetrakis [1,3,-diethyl-2imidazoyl] manganese-porphyrin pentachloride [TDE-2,5-IP]) effectively reduces NF-B binding to DNA, the release of cytokines and chemokines, and PARP activation in islet cells, resulting in higher survival and better insulin release. These findings support the concept that the isolation process predisposes islets to subsequent damage and functional impairment. Blocking oxidative stress can be beneficial in reducing islet vulnerability and can potentially have a significant impact on transplantation outcome.

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Activation of pancreatic acinar cells on isolation from tissue: cytokine upregulation via p38 MAP kinase

Cited by 128 publications

References 41 publications

IL-6 Secretion by Human Pancreatic Periacinar Myofibroblasts in Response to Inflammatory Mediators

IL-6 Secretion by Human Pancreatic Periacinar Myofibroblasts in Response to Inflammatory Mediators

Effect of NF-κB and p38 MAPK in activated monocytes/macrophages on pro-inflammatory cytokines of rats with acute pancreatitis

Response of Human Islets to Isolation Stress and the Effect of Antioxidant Treatment

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