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

被引:40
作者
Tietz, Anne Barbara
Malo, Antje
Diebold, Joachim
Kotlyarov, Alexey
Herbst, Andreas
Kolligs, Frank T.
Brandt-Nedelev, Barbara
Halangk, Walter
Gaestel, Matthias
Goeke, Burkhard
Schaefer, Claus
机构
[1] Univ Munich, Klinikum Grosshadern, Dept Internal Med 2, D-81377 Munich, Germany
[2] Univ Munich, Dept Pathol, D-81377 Munich, Germany
[3] Hannover Med Sch, Dept Biochem, D-3000 Hannover, Germany
[4] Otto Von Guericke Univ, Dept Surg, Div Expt Surg, Magdeburg, Germany
来源
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2006年 / 290卷 / 06期
关键词
cytokines; MAPKAP kinase; actin cytoskeleton; inflammation;
D O I
10.1152/ajpgi.00530.2005
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
引用
收藏
页码:G1298 / G1306
页数:9
相关论文
共 36 条
[1]   The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumour necrosis factor [J].
Beyaert, R ;
Cuenda, A ;
VandenBerghe, W ;
Plaisance, S ;
Lee, JC ;
Haegeman, G ;
Cohen, P ;
Fiers, W .
EMBO JOURNAL, 1996, 15 (08) :1914-1923
[2]   Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome [J].
Bhatia, M ;
Moochhala, S .
JOURNAL OF PATHOLOGY, 2004, 202 (02) :145-156
[3]  
Bhatia M, 2001, Curr Opin Investig Drugs, V2, P496
[4]   Activation of pancreatic acinar cells on isolation from tissue: cytokine upregulation via p38 MAP kinase [J].
Blinman, TA ;
Gukovsky, I ;
Mouria, M ;
Zaninovic, V ;
Livingston, E ;
Pandol, SJ ;
Gukovskaya, AS .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2000, 279 (06) :C1993-C2003
[5]   Cytokines and acute pancreatitis [J].
Brady, M ;
Christmas, S ;
Sutton, R ;
Neoptolemos, J ;
Slavin, J .
BEST PRACTICE & RESEARCH CLINICAL GASTROENTEROLOGY, 1999, 13 (02) :265-289
[6]   Absence of endogenous interleukin-6 enhances the inflammatory response during acute pancreatitis induced by cerulein in mice [J].
Cuzzocrea, S ;
Mazzon, E ;
Dugo, L ;
Centorrino, T ;
Ciccolo, A ;
McDonald, MC ;
De Sarro, A ;
Caputi, AP ;
Thiemermann, C .
CYTOKINE, 2002, 18 (05) :274-285
[7]   TNF but not IL-1 decreases pancreatic acinar cell survival without affecting exocrine function: A study in the perfused human pancreas [J].
Denham, W ;
Yang, J ;
Fink, G ;
Denham, D ;
Carter, G ;
Bowers, V ;
Norman, J .
JOURNAL OF SURGICAL RESEARCH, 1998, 74 (01) :3-7
[8]   MAPKAP KINASE-2 IS ACTIVATED BY HEAT-SHOCK AND TNF-ALPHA - IN-VIVO PHOSPHORYLATION OF SMALL HEAT-SHOCK PROTEIN RESULTS FROM STIMULATION OF THE MAP KINASE CASCADE [J].
ENGEL, K ;
AHLERS, A ;
BRACH, MA ;
HERRMANN, F ;
GAESTEL, M .
JOURNAL OF CELLULAR BIOCHEMISTRY, 1995, 57 (02) :321-330
[9]   JAK and STAT proteins are expressed and activated by IFN-γ in rat pancreatic acinar cells [J].
Gallmeier, E ;
Schäfer, C ;
Moubarak, P ;
Tietz, A ;
Plössl, I ;
Huss, R ;
Göke, B ;
Wagner, ACC .
JOURNAL OF CELLULAR PHYSIOLOGY, 2005, 203 (01) :209-216
[10]  
Gomez-Cambronero L. G., 2002, Current Drug Targets - Inflammation and Allergy, V1, P393, DOI 10.2174/1568010023344544