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

Lidiya S. Orlichenko, Jaideep Behari, Tzu Hsuan Yeh, Shiguang Liu, Donna B. Stolz, Ashok Saluja, Vijay P. Singh

Research output: Contribution to journalArticle

31 Citations (Scopus)

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-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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume299
Issue number4
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

Fingerprint

Chemokine CXCL2
CXC Chemokines
Keratinocytes
Transcription Factor AP-1
Cytokines
Acinar Cells
Up-Regulation
Ceruletide
Pancreatitis
Protein Kinase C
Inflammation
Calcium
Chemotactic Factors
Genetic Promoter Regions
Neutrophils
Transcription Factors

Keywords

  • Acinar
  • Activator protein-1
  • Keratinocyte cytokine
  • Macrophage inflammatory protein-2
  • Nuclear factor-κB

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology
  • Medicine(all)

Cite this

Transcriptional regulation of CXC-ELR chemokines KC and MIP-2 in mouse pancreatic acini. / Orlichenko, Lidiya S.; Behari, Jaideep; Yeh, Tzu Hsuan; Liu, Shiguang; Stolz, Donna B.; Saluja, Ashok; Singh, Vijay P.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 299, No. 4, 01.10.2010.

Research output: Contribution to journalArticle

Orlichenko, Lidiya S. ; Behari, Jaideep ; Yeh, Tzu Hsuan ; Liu, Shiguang ; Stolz, Donna B. ; Saluja, Ashok ; Singh, Vijay P. / Transcriptional regulation of CXC-ELR chemokines KC and MIP-2 in mouse pancreatic acini. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2010 ; Vol. 299, No. 4.
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