Transcriptional regulation of CXC-ELR chemokines KC and MIP-2 in mouse pancreatic acini

Am J Physiol Gastrointest Liver Physiol. 2010 Oct;299(4):G867-76. doi: 10.1152/ajpgi.00177.2010. Epub 2010 Jul 29.


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-κB, 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-κB 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-κB 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-κB inhibition completely prevented upregulation of KC but not MIP-2. Complete suppression of MIP-2 upregulation required dual inhibition of NF-κB 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-κB and AP-1 in these cells. Thus dual inhibition of NF-κB and AP-1 may be a more successful strategy to reduce inflammation in pancreatitis than targeting NF-κB alone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium
  • Ceruletide / metabolism
  • Ceruletide / pharmacology
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / metabolism*
  • Chemokine CXCL2 / genetics
  • Chemokine CXCL2 / metabolism*
  • Inflammation / metabolism
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • Pancreas / cytology
  • Pancreas / metabolism*
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / pharmacology
  • Protein Kinase C
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tissue Culture Techniques
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription, Genetic / physiology*
  • Up-Regulation


  • Chemokine CXCL1
  • Chemokine CXCL2
  • Cxcl1 protein, mouse
  • Cxcl2 protein, mouse
  • NF-kappa B
  • RNA, Messenger
  • Transcription Factor AP-1
  • 9-deoxy-delta-9-prostaglandin D2
  • Ceruletide
  • Protein Kinase C
  • Prostaglandin D2
  • Calcium