Extracellular heat-shock protein 70 aggravates cerulein-induced pancreatitis through toll-like receptor-4 in mice.
BACKGROUND
In patients suffering from acute pancreatitis, the pathogenesis is not completely understood, and several recent studies in vitro suggested that heat shock proteins might play an important role in cell signaling. To investigate the possible role of extracellular heat shock protein 70 (Hsp70) in pancreatitis, toll-like receptor-4 (TLR4)-deficient and wild-type mice were administered with exogenous Hsp70 during the course of cerulein-induced pancreatitis (CIP).


METHODS
Acute pancreatitis was induced by 5 intraperitoneal injections of cerulein at hourly intervals, and then treated with recombinant Hsp70 through the caudal vein 4 hours after the start of cerulein injections. Subsequently serum amylase and serum cytokines levels were detected. Histologic alteration of the pancreas was evaluated. Tumor necrosis factor alpha (TNF-alpha) concentrations and myeloperoxidase (MPO) activity in both pancreas and lungs were analyzed. The nuclear factor kappa B (NF-kappaB) activation in pancreatic tissue was measured using a sensitive RelA enzyme-linked immunosorbent assay.


RESULTS
Treatment with recombinant Hsp70 to wild-type mice in CIP resulted in significant aggravation of inflammation in pancreas, elevated levels of serum cytokines, up-regulation of pulmonary MPO activity and increase of lung tissues TNF-alpha concentrations. In contrast, treatment with Hsp70 to TLR4-deficient mice had little effect on serum cytokines levels, pancreatic inflammation, pulmonary MPO activity and TNF-alpha concentrations.


CONCLUSIONS
The results suggest that extracellular Hsp70 might induce systemic inflammatory response syndrome (SIRS)-like response in vivo and TLR4 might be involved in the Hsp70-mediated activation of inflammatory reaction in the progression of CIP without infection.
Song
Jun-Min
JM
Department of General Surgery III and Institute of Digestive Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Liu
Hong-Xiang
HX
Li
Yuan
Y
Zeng
Yu-Jian
YJ
Zhou
Zong-Guang
ZG
Liu
Hai-Yi
HY
Xu
Bing
B
Wang
Ling
L
Zhou
Bin
B
Wang
Rong
R
D000208:Acute Disease; D000818:Animals; D002108:Ceruletide / Q000633:toxicity*; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010195:Pancreatitis / Q000209:etiology*; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D018840:HSP70 Heat-Shock Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002108:Ceruletide