Tohoku J. Exp. Med., 2009, 217(4)

Down-Regulation of Tumor Necrosis Factor-Associated Factor 6 Is Associated with Progression of Acute Pancreatitis Complicating Lung Injury in Mice

XIANGYU ZHOU,¹ YUAN LI,¹ JUNLI DING,¹ LING WANG,¹ RONG WANG,¹ BING ZHOU,¹ JUN GU,¹ XIAOFENG SUN² and ZONGGUANG ZHOU¹

¹Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, P.R. China
²Department of Oncology, Institute of Biomedicine and Surgery, University of Linköping, Linköping, Sweden

Acute lung injury is one of the critical complications of acute pancreatitis (AP). Tumor necrosis factor-associated factor 6 (TRAF6) is a key adaptor that regulates various inflammatory signaling pathways, including those mediated by Toll-like receptors (TLRs). This study was performed to investigate the potential role of TRAF6 in the pathogenesis of AP and pancreatitis-associated acute lung injury using a mouse model of caerulein-induced AP (CAP). CAP was induced by intraperitoneal injection of caerulein hourly for 7 times (50μg/kg), and control mice were treated with saline of the same volume. Typical pancreatic and lung inflammation was observed in the early stage (1 h) of CAP, as judged by morphological changes. Likewise, in CAP mice, the pancreatic myeloperoxidase activity and serum levels of interleukin-6 and interleukin-10 were significantly increased after 2 h, peaked at 4h, and then decreased by 24 h. The expression of TRAF6 was then studied by real time-PCR, immunohistochemistry, and Western blot analysis. Compared with control group, TRAF6 mRNA level was decreased in CAP group within the first 12 h, and then significantly increased after 24 h, which was in accordance with the protein level detected by Western blot analysis and immunohistochemistry. Moreover, TRAF6 protein was expressed in both pancreatic acinar cells and lung bronchial epithelial cells. In conclusion, the down-regulation of TRAF6 was associated with increased inflammatory severity in the pancreas and lung, suggesting that TRAF6 is involved in the anti-inflammatory process during AP. TRAF6 may be a potential molecular target for treating AP.

keywords —— inflammation; pathogenesis; acute pancreatitis; tumor necrosis factor-associated factor 6; acute lung injury.

© 2009 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2009, 217, 279-285

Correspondence: Zongguang Zhou, M.D., PH.D., Institute of Digestive Surgery and State Key Laboratory of Biotherapy, Institute of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.

e-mail: Zhou767@163.com