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Cyclic AMP dysregulates intestinal epithelial cell restitution through PKA and RhoA. Inflamm Bowel Dis 2012 Jun;18(6):1081-91

Date

10/14/2011

Pubmed ID

21993975

Pubmed Central ID

PMC3258471

DOI

10.1002/ibd.21898

Scopus ID

2-s2.0-84861333263   21 Citations

Abstract

BACKGROUND: Mucosal homeostasis is dependent on the establishment and maintenance of the cell-cell contacts that comprise the physiological barrier. Breaks in the barrier are linked to multiple diseases such as inflammatory bowel disease. While increased cyclic adenosine monophosphate (cAMP) levels limit inflammation by decreasing leukocyte infiltration, the effects of elevated cAMP on intestinal epithelial repair are unknown.

METHODS: Restitution in animals administered rolipram was monitored by microscopic examination after laser wounding of the intestinal epithelium or in mice treated with dextran sodium sulfate (DSS). In vitro analysis was conducted using IEC6 and T84 cells to determine the role of elevated cAMP in altering Rho-dependent cellular migration signaling pathways.

RESULTS: We show that treatment with rolipram, forskolin, and cAMP analogs decrease intestinal epithelial cell migration in vitro. In vivo cell imaging revealed that increased cAMP resulted in a decreased cellular migration rate, with cells at the edge displaying the highest activity. As expected, elevated cAMP elicited increased protein kinase A (PKA) activity, in turn resulting in the inactivation and sequestration of RhoA and decreased actin reorganization. The ablation of restitution by cAMP was not restricted to cell culture, as forskolin and rolipram treatment significantly decreased epithelial microwound closure induced by the two photon confocal injury model.

CONCLUSIONS: Together, these data suggest that administration of cAMP-elevating agents paradoxically decrease infiltration of damage-causing leukocytes while also preventing epithelial repair and barrier maintenance. We propose that treatment with cAMP-elevating agents severely limits mucosal reepithelialization and should be contraindicated for use in chronic inflammatory bowel disorders.

Author List

Zimmerman NP, Kumar SN, Turner JR, Dwinell MB

Authors

Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Suresh Kumar PhD Associate Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Movement
Cells, Cultured
Colforsin
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Humans
Intestinal Mucosa
Lasers
Mice
Phosphodiesterase 4 Inhibitors
Phosphorylation
Rats
Rolipram
Signal Transduction
Wound Healing
rhoA GTP-Binding Protein
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a