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Potential role of the TLR4/IRAK-4 signaling pathway in the pathophysiology of acute pancreatitis in mice

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Abstract

Objective and design

Toll-like receptor 4 (TLR4) is potentially associated with acute pancreatitis (AP), but its exact role remains controversial. IL-1 receptor-associated kinase 4 (IRAK-4) is a common mediator of Toll-like receptors pathways, with an essential role in transducing downstream signals. This study investigates the potential role of the TLR4 pathway, in particular IRAK-4, in a murine model of AP.

Methods

Acute pancreatitis was induced in wild-type and TLR4-deficient mice by intraperitoneal injections of caerulein (50 μg/kg). Pancreatic pathological scores and myeloperoxidase activity were dynamically measured, along with pancreatic TLR4 and IRAK-4 mRNA and protein.

Results

In wild-type mice, pathological scores and myeloperoxidase activity were rapidly increased at 1, 2 and 4 h, followed by alleviation at 12 and 24 h. In TLR4-deficient mice, they were slightly increased within 2 h, but became more severe at 12 and 24 h. IRAK-4 mRNA and protein were significantly down-regulated at 1, 2 and 4 h in wild-type mice. Unexpectedly, TLR4-deficient mice showed more profound reductions of IRAK-4 mRNA and protein at the same time.

Conclusions

TLR4 deficiency delayed the initiation of pancreatitis, implying a potential role for TLR4 during AP. IRAK-4 might function during AP, but independently of TLR4.

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Acknowledgments

This work was supported by grants from National Natural Science Fund of China (No. 30571811, No. 30400434) and China Medical Board (CMB) grant (No. 96636). We acknowledge the skilled technical assistance of Jun-Gu and Lan-Zhan.

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Authors and Affiliations

  1. State Key Laboratory of Biotherapy, Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 37 Guo-Xue-Xiang, 610041, Chengdu, Sichuan, People’s Republic of China

    Jun-Li Ding, Yuan Li, Xiang-Yu Zhou, Ling Wang, Bin Zhou, Rong Wang, Hong-Xiang Liu & Zong-Guang Zhou

  2. Department of Gastroenterological Surgery, State Key Laboratory of Biotherapy, Institute of Digestive Surgery, West China Hospital, Sichuan University, No. 37 Guo-Xue-Xiang, 610041, Chengdu, Sichuan, People’s Republic of China

    Zong-Guang Zhou

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  1. Jun-Li Ding
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  2. Yuan Li
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  4. Ling Wang
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  5. Bin Zhou
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  6. Rong Wang
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Correspondence to Zong-Guang Zhou.

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Responsible Editor: M.J. Parnham.

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Ding, JL., Li, Y., Zhou, XY. et al. Potential role of the TLR4/IRAK-4 signaling pathway in the pathophysiology of acute pancreatitis in mice. Inflamm. Res. 58, 783–790 (2009). https://doi.org/10.1007/s00011-009-0048-0

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  • DOI: https://doi.org/10.1007/s00011-009-0048-0

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