Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation

Kellie E. Cunningham, Elizabeth A. Novak, Garret Vincent, Vei Shaun Siow, Brian D. Griffith, Sarangarajan Ranganathan, Matthew R. Rosengart, Jon D. Piganelli, Kevin P. Mollen

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing worldwide. IBD is known to be multifactorial, but inflammatory signaling within the intestinal epithelium and a subsequent failure of the intestinal epithelial barrier have been shown to play essential roles in disease pathogenesis. CaMKIV is a multifunctionalproteinkinase associatedwithinflammation and cell cycle regulation.CaMKIVhasbeen extensively studied in autoimmune diseases, but a role in idiopathic intestinal inflammation has not been described. In this study, active CaMKIV was highly expressed within the intestinal epithelium of humans with ulcerative colitis and wild-type (WT) mice with experimental induced colitis. Clinical disease severity directly correlates with CaMKIV activation, as does expression of proinflammatory cytokines and histologic features of colitis. In WT mice, CaMKIV activation is associated with increases in expression of 2 cell cycle proarrest signals: p53 and p21. Cell cycle arrest inhibits proliferation of the intestinal epithelium and ultimately results in compromised intestinal epithelial barrier integrity, further perpetuating intestinal inflammation during experimental colitis. Using a CaMKIV null mutant mouse, we demonstrate that a loss of CaMKIV protects against murine DSS colitis. Small molecules targeting CaMKIV activation may provide therapeutic benefit for patients with IBD.

Original languageEnglish
Pages (from-to)1330-1346
Number of pages17
JournalFASEB Journal
Volume33
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • CREB
  • Inflammatory bowel disease
  • Intestinal epithelial barrier
  • Intracellular calcium signaling

Fingerprint

Dive into the research topics of 'Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation'. Together they form a unique fingerprint.

Cite this