The initial phase of AP involves disruption of acinar cells and pancreatic autodigestion, followed by activation of local inflammatory cells example and release of proinflammatory cytokines, among which the interleukin-1 (IL-1) system, activated early during AP, was shown to play a pivotal role in promoting local tissue destruction and extrapancreatic organ failure.3 Indeed, blockade of the IL-1 receptor (IL-1R) is able to attenuate the propagation of pancreatic injury and associated inflammation in murine models.4,5 A newly identified member of the IL-1 family, IL-33 [also known as interleukin-1 family member 11 (IL-1F11)] is characterized by a dual function. IL-33 can either regulate gene transcription in the nucleus, dampening proinflammatory signaling,6,7 or be released as an alarmin by cells undergoing necrosis, triggering inflammation in an autocrine or paracrine manner.

8,9 IL-33 signals through a receptor complex by binding to the ST2 receptor10 and recruiting the coreceptor IL-1R accessory protein (IL-1R AcP).11 The ST2 receptor belongs to the family of Toll-like/IL-1 receptor (TIR) domain receptors and is expressed on Th2 lymphocytes, mast cells, and some epithelial cells.12 The ST2 gene (IL1RL1) encodes two isoforms of ST2 proteins: ST2L, a transmembrane form, and soluble ST2 (sST2), a secreted form that can serve as a decoy receptor by binding IL-33 and thus inhibiting its signaling through ST2L.13 Along with promoting a Th2 response, ST2 has been shown to sequester MyD88, the first signaling molecule activated by TLR4 and IL-1R1.

This effect has identified ST2 as a key regulator in endotoxin tolerance.14 Given that the IL-1 cytokine family is activated early in the course of AP, that speculation exists concerning secretion of alarmins during AP necrosis, and that MyD88 might regulate the AP inflammatory storm, we investigated whether the IL-33-ST2 pathway might be involved in AP in humans and in mice. Materials and Methods Patients Plasma from 44 patients admitted to our institution for an episode of AP between 2005 and 2008 was studied. Inclusion criteria were, first, the taking of the blood sample less than 24 hours after onset of symptoms, and then at least two of the following: typical pain, amylase and lipase concentrations at least thrice the upper normal limit, and compatible modifications observed under imaging.

Clinical characteristics of these patients Brefeldin_A are given in Table 1. Table 1 Characteristics of Patients with Acute Pancreatitis The etiologies of AP were biliary for 61% of the patients, alcoholic for 21%, and miscellaneous (including hypertriglyceridemia, unknown or familial etiology, and intraductal papillary mucinous tumor) for 18%. Patients with chronic pancreatitis were excluded. Necrotizing pancreatitis was defined by the absence of enhancement of pancreatic tissue on contrast-injected computed tomography or magnetic resonance imaging.