Toll-like Receptor 4 Detected in Exocrine Pancreas and the Change of Expression in Cerulein-induced Pancreatitis

Li, Yuan; Zhou, Zong-Guang; Xia, Qingjie; Zhang, Jie; Li, Hongguang; Cao, Gui-qun; Wang, Rong; Lu, Yi-Lu; Hu, Tuo

doi:10.1097/01.mpa.0000160959.21580.41

Cited by 48 publications

(33 citation statements)

References 24 publications

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“…Representative FACS plots are shown from 3 independent experiments (n ≥ 3 per group). (18). In order to determine the contribution of and CORM-2's effect on hematopoietic TLR4 in AP, we generated chimeric mice by engrafting WT recipients with either WT or TLR4 KO BM cells (WT→WT or TLR4 KO→WT mice, respectively).…”

Section: Corm-2 Ameliorates Established Experimental Apmentioning

confidence: 99%

Carbon monoxide–based therapy ameliorates acute pancreatitis via TLR4 inhibition

Xue¹,

Habtezion²

2013

J. Clin. Invest.

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The protective role of hemeoxygenase-1 (HO-1) in various inflammatory conditions is mediated in part by its products, carbon monoxide (CO) and biliverdin. Here we investigated a therapeutic role for CO and COprimed cells in acute pancreatitis (AP). In a mouse model of AP, treatment with CO-releasing molecule-2 (CORM-2) decreased mortality, pancreatic damage, and lung injury. CORM-2 decreased systemic inflammatory cytokines, suppressed systemic and pancreatic macrophage TNF-α secretion, and inhibited macrophage TLR4 receptor complex expression. In both human and mouse cells, CORM-2 inhibited endogenous and exogenous ligand-dependent TLR4 activation, which indicates that CORM-2 could be therapeutic for both early and late stages of AP, which involve sterile-and endotoxin-mediated inflammation, respectively. Mice engrafted with TLR4-deficient hematopoietic cells were protected against caerulein-induced AP. In the absence of leukocyte TLR4 expression, CORM-2 did not confer additional protection, which indicates that CORM-2-dependent effects are mediated via suppression of macrophage TLR4 activation. We determined that CO was directly responsible for the protective effects of CORM-2 in AP, as inactive forms of CORM-2 were ineffective. Importantly, adoptive transfer of CORM-2-primed cells reduced AP. Such a therapeutic approach would translate the beneficial effects of CO-based therapies, avoiding CO-or CO-RM-mediated toxicities in AP and a wide range of diseases.

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Section: Corm-2 Ameliorates Established Experimental Apmentioning

confidence: 99%

Carbon monoxide–based therapy ameliorates acute pancreatitis via TLR4 inhibition

Xue¹,

Habtezion²

2013

J. Clin. Invest.

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“…A report has indicated that in the early stage of acute pancreatitis, the expression levels of TLR4, TNF-, and IL-6 in pancreas of acute pancreatitis patients are significantly higher than those in the control ones, the level of plasma TNF-in acute pancreatitis patients increases subsequently, and the increase of plasma TNF-level is positively correlated with the expression of TLR4, suggesting that the up-regulation of TLR4 expression on the surface of peripheral blood monocytes in patients with early acute pancreatitis might be associated with the activation of the innate immune system in the early stage of the disease [150]. Results of animal experiments have shown that TLR4 messenger RNA is also up-regulated in the pancreas of rats with cerulein-induced edematous pancreatitis in the early stage, the serum levels of cytokines such as TNF-are subsequently elevated, and the two phenomena are correlated [151].…”

Section: Toll-like Receptor-4 (Tlr4)mentioning

confidence: 76%

Microcirculatory Disturbances in the Pathogenesis of Acute Pancreatitis

Uhlmann¹

2012

Acute Pancreatitis

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“…Immunoreactivity of IL-6 has been detected in acinar, pancreatic islet, and duct cells during human pancreatitis (Jablonowska et al, 2008). Experimental induction of AP leads to elevated expression of toll-like receptor 4 in pancreatic ductal epithelium, vascular endothelium, and islet, further complicating the inflammatory signals (Li et al, 2005). Taken these findings together, an intricate cross talk between pancreatic cells in regulating inflammatory response might exist.…”

Section: Redox-sensitive Erk-induced Pancreatic Inflammation 453mentioning

confidence: 88%

Involvement of Redox-Sensitive Extracellular-Regulated Kinases in Angiotensin II-Induced Interleukin-6 Expression in Pancreatic Acinar Cells

Chan

Leung²

2009

J Pharmacol Exp Ther

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Angiotensin II has been shown to play a role in the pathogenesis of acute pancreatitis (AP). The present investigation aimed at elucidating redox-sensitive mechanistic pathway involved in proinflammatory actions of angiotensin II during an episode of AP; in particular, the regulation of expression of cytokine interleukin (IL)-6. Exogenous angiotensin II induced IL-6 expression, activation of extracellular-regulated kinase (ERK) 1/2, and superoxide generation in pancreatic acinar cell line AR42J, which were reversed by the angiotensin II type 1 (AT 1 ) receptor antagonist, losartan (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl) benzyl] imidazole-5-methanol monopotassium salt, C 22 H 23 ClN 6 O). Pharmacological blockade of ERK1/2 improved angiotensin II-induced IL-6 expression. Moreover, angiotensin II-induced ERK1/2 activation was suppressed by antioxidant, indicating that redox-regulated ERK1/2 mediates the cytokine expression. cAMP-responsive element-binding protein (CREB) might be involved in ERK1/2-induced IL-6 expression because phosphorylation of CREB was observed after angiotensin II treatment, which was reversed by losartan and the ERK1/2 inhibitor. These results were in close agreement with the in vivo findings using an obstructive model of AP. Obstruction of the common biliopancreatic duct time-dependently enhanced angiotensinogen levels, which correlated well with superoxide generation, ERK1/2 and CREB phosphorylation, and subsequent IL-6 expression. It is more important that changes in these parameters were antagonized by prophylactic administration of losartan. These in vitro and in vivo results indicate that angiotensin II induces redox-regulated ERK1/2 and CREB activation, thus leading to IL-6 expression in an AT 1 receptormediated manner in pancreatic acinar cells during the pathogenesis of AP.

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Toll-like Receptor 4 Detected in Exocrine Pancreas and the Change of Expression in Cerulein-induced Pancreatitis

Abstract: TLR4 protein was expressed in pancreas and localized to epithelial (pancreatic duct) or endothelial (vessels) tissues; TLR4 responded favorably to the inflammatory process, and the change of expression was characterized as a rapid up-regulation in the early stage of CIP.

Cited by 48 publications

References 24 publications

Carbon monoxide–based therapy ameliorates acute pancreatitis via TLR4 inhibition

Carbon monoxide–based therapy ameliorates acute pancreatitis via TLR4 inhibition

Microcirculatory Disturbances in the Pathogenesis of Acute Pancreatitis

Involvement of Redox-Sensitive Extracellular-Regulated Kinases in Angiotensin II-Induced Interleukin-6 Expression in Pancreatic Acinar Cells

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