In addition, these data were consistent with our in vivo experiments, in which the tryptase concentration increased in sera of mice during CDE-induced AP, and significantly more in Il1rl1?/? http://www.selleckchem.com/products/Belinostat.html mice. We therefore speculate that ST2 plays a key role in regulation of the severity of pancreatitis. IL-33 has been reported to be expressed mainly by endothelial cells, fibroblasts, adipocytes, synovium,45 and, more recently and specifically, by pancreatic myofibroblasts46 and cardiac fibroblasts.13 In the present study, we showed that pancreatic acinar cells constitutively express IL-33 mRNA and protein, and that AP is associated with an increase in the serum concentration of IL-33 in mice. In humans, however, IL-33 was detectable in only 9 of the 44 patients and did not correlate with AP severity (data not shown).

Functions and secretion mechanisms of this newly identified cytokine10 are not yet fully elucidated. In asthma, arthritis, and anaphylactic shock, exogenous IL-33 was shown to exacerbate the disease through ST2 activation.24,47,48 In contrast, activation of ST2 leading to sequestration of MyD8814 or inhibition of cardiomyocyte hypertrophy13 suggests a protective role for IL-33. It has been described as a double agent, acting in the nucleus as an inhibitor of NF-��B-dependent gene expression6,7 or in a paracrine manner as an alarmin.8,9 Given that IL-33 is constitutively expressed in the pancreas and that its levels increase in serum during AP, our results suggest that IL-33 is implicated in AP and is more likely to act as an endogenous danger signal, like high mobility group protein B1 (HMGB1).

49 Enoksson et al9 recently identified mast cells as important contributors to early cell injury responses and acute inflammation. They confirmed the central role played by IL-33 released by necrotizing cells in mast cell proinflammatory activation. Moreover, two recent reports strongly implicate IL-33 involvement in human chronic pancreatitis. One study showed that pancreatic stellate cells express IL-33 and ST2,50 and the other reported the expression of these molecules by pancreatic myofibroblasts.46 Because we demonstrated that the ST2 pathway is protective in the acute phase of pancreatitis, we speculate that, as the disease evolves to a chronic form, this pathway might become noxious by promoting fibrosis,51 but this will require confirmation in vivo.

In conclusion, we have demonstrated for the first time the involvement of the IL-33-ST2 pathway in the pathophysiology of AP in humans, with a rise in sST2 levels in human serum during AP and its correlation with disease severity. In mice, we show that ST2 plays a protective role in AP and is expressed by peritoneal mast cells, which are activated during GSK-3 AP. Finally, we demonstrate that IL-33, the ST2 ligand, is expressed by murine pancreatic acinar cells and is released during AP.