Gene deletion of MK2 inhibits TNF-alpha and IL-6 and protects against cerulein-induced pancreatitis.

Abstract

Inflammatory effects contribute to the pathogenesis of pancreatitis. Clearly, proinflammatory cytokines like TNF-alpha and IL-6 are involved in this process and the associated systemic complications. The MAPKAPK-2 (MK2) signaling pathway is involved in cytokine gene expression. Therefore, we hypothesized that blockade of this pathway inhibits the expression of proinflammatory cytokines and thereby protects against pancreatitis. To investigate this, we used an in vivo mouse model with a homozygous deletion of the MK2 gene. Pancreatitis was induced by injection of cerulein. The severity was determined by measuring serum lipase, pancreatic trypsin activation, pancreatic edema, and morphological changes by quantitative scoring of histological sections. Systemic inflammation was evaluated by measuring myeloperoxidase activity in lung tissue. Serum levels of TNF-alpha and IL-6 were measured using an ELISA, and mRNA levels were identified using RT-PCR and subsequent quantitative PCR analysis. Pancreatitis in animals with deletion of the MK2 gene is less severe and accompanied with reduced serum levels of TNF-alpha and IL-6. Pancreatic mRNA levels revealed a fourfold reduction of IL-6 mRNA expression in MK2 -/- mice. Effects were associated with suppression of pancreatic trypsin activity and reduced acinar cell injury. In summary, these data show that gene deletion of MK2 ameliorates cerulein-induced pancreatitis. TNF-alpha and IL-6 signaling is mediated by the MK2 pathway and therefore crucial for the regulatory inflammatory processes. TNF-alpha expression is supposably regulated by a posttranscriptional mechanism, whereas IL-6 expression is most likely regulated by transcriptional effects.

• Authors: Anne Barbara Tietz, Antje Malo, Joachim Diebold, Alexey Kotlyarov, Andreas Herbst, Frank T Kolligs, Barbara Brandt-Nedelev, Walter Halangk, Matthias Gaestel, Burkhard Göke, Claus Schäfer
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 290 Issue 6 Pg. G1298-306 (Jun 2006) ISSN: 0193-1857 [Print] United States
• PMID: 16423921 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Intracellular Signaling Peptides and Proteins
• Tumor Necrosis Factor-alpha
• Ceruletide
• Protein Kinases
• MAP-kinase-activated kinase 2
• Protein Serine-Threonine Kinases

Topics

• Animals
• Ceruletide
• Disease Models, Animal
• Gene Deletion
• Interleukin-6 (metabolism)
• Intracellular Signaling Peptides and Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pancreatitis, Acute Necrotizing (chemically induced, metabolism, pathology)
• Protein Kinases (genetics, metabolism)
• Protein Serine-Threonine Kinases
• Tumor Necrosis Factor-alpha (metabolism)