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Transcriptional regulation of CXC-ELR chemokines KC and MIP-2 in mouse pancreatic acini
- Source :
- The American Journal of Physiology. Oct, 2010, Vol. 299 Issue 4, pG867, 10 p.
- Publication Year :
- 2010
-
Abstract
- Neutrophils and their chemoattractants, the CXC-ELR chemokines keratinocyte cytokine (KC) and macrophage inflammatory protein-2 (MIP-2), play a critical role in pancreatitis. While acute pancreatitis is initiated in acinar cells, it is unclear if these are a source of CXC-ELR chemokines. KC and MIP-2 have NF-[kappa]B, activator protein-1 (AP-1) sites in their promoter regions. However, previous studies have shown increased basal and reduced caerulein-induced AP-1 activation in harvested pancreatic tissue in vitro, which limits interpreting the caerulein-induced response. Moreover, recent studies suggest that NF-[kappa]B silencing in acinar cells alone may not be sufficient to reduce inflammation in acute pancreatitis. Thus the aim of this study was to determine whether acinar cells are a source of KC and MIP-2 and to understand their transcriptional regulation. Primary overnight-cultured murine pancreatic acini were used after confirming their ability to replicate physiological and pathological acinar cell responses. Upstream signaling resulting in KC, MIP-2 upregulation was studied along with activation of the transcription factors NF-[kappa]B and AP-1. Cultured acini replicated critical responses to physiological and pathological caerulein concentrations. KC and MIP-2 mRNA levels increased in response to supramaximal but not to physiological caerulein doses. This upregulation was calcium and protein kinase C (PKC), but not cAMP, dependent. NF-[kappa]B inhibition completely prevented upregulation of KC but not MIP-2. Complete suppression of MIP-2 upregulation required dual inhibition of NF-[kappa]B and AP-1. Acinar cells are a likely source of KC and MIP-2 upregulation during pancreatitis. This upregulation is dependent on calcium and PKC. MIP-2 upregulation requires both NF-[kappa]B and AP-1 in these cells. Thus dual inhibition of NF-[kappa]B and AP-1 may be a more successful strategy to reduce inflammation in pancreatitis than targeting NF-[kappa]B alone. keratinocyte cytokine; macrophage inflammatory protein-2; activator protein-1; nuclear factor-[kappa]B; acinar doi: 10.1152/ajpgi.00177.2010.
Details
- Language :
- English
- ISSN :
- 00029513
- Volume :
- 299
- Issue :
- 4
- Database :
- Gale General OneFile
- Journal :
- The American Journal of Physiology
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.240912634