Regulation of Hsp60 and the role of MK2 in a new model of severe experimental pancreatitis

MK2 plays a pivotal role in regulating signal transduction pathways of cytokines. It has been shown that induction and expression of several Heat shock proteins (HSPs) can protect against pancreatitis. Little is known about regulation and potential protective effects of Hsp60. The objective of this study was to investigate the role of MK2 and the regulation of HSP60 in the pathogenesis of a new model of severe acute pancreatitis (AP). To elucidate the role of MK2, mice with a homozygous deletion of the MK2 gene were used (MK2 -/-). Severe AP was induced by combined i.p. injections of cerulein with LPS. Severity of AP was assessed by examination of biochemical parameters and by histological analysis. Repeated injections of cerulein alone or in combination with LPS resulted in local inflammatory responses in the pancreas and in systemic inflammatory changes, with animals in the Cer+LPS group being much more severe. Compared to the C57Bl mice, the MK2-/- mice presented with significant milder pancreatitis, showing lower serum amylase and IL-6 levels, decreased trypsinogen and lung MPO activity. The mice injected with LPS alone displayed neither pancreatic inflammatory responses nor alteration of pancreatic enzyme activities, but evidently elevated serum IL-6 levels and increased lung MPO activity. In contrast, in MK2 -/- mice, these changes were much milder than those in wild-type mice. Analysis of heat shock protein expression showed increased expression of Hsp25 and Hsp60. Especially Hsp60 demonstrated robustly elevated expression in the Cer+LPS treated mice in both, MK2 -/- and wild-type mice compared to saline or cerulein treated animals. The increased levels of HSP60 expression in MK2-/- mice were slightly higher, but not significant, than in wild-type mice. These results revealed that deletion of the MK2 gene ameliorates the severity of acute pancreatitis and systemic inflammation in a more severe systemic inflammatory model of AP with repeated injections of cerulein in combination with injection of LPS. The obtained data support the hypothesis that MK2 signalling pathways participate in the multi-factorial regulation of inflammatory responses in AP, possibly including the regulation of certain stress proteins, in particular HSP25 and HSP60.