Imatinib mesylate alleviates diarrhea in a mouse model of intestinal allergy.
BACKGROUND
When sensitized epicutaneously and challenged orally with ovalbumin, Balb/c mice develop allergen-induced diarrhea. As mast cells play important roles in diarrhea, we studied whether allergic diarrhea could be alleviated with imatinib mesylate.


METHODS
Balb/c mice were sensitized and challenged with ovalbumin and treated orally with imatinib. Cytokine mRNA expressions were determined with quantitative RT-PCR and numbers of small intestinal mast cells determined by staining for chloroacetate esterase and mucosal mast cell protease-1. Immunofluorescence staining was used to assess the intestinal CCL1 expression.


RESULTS
Ovalbumin-sensitized and challenged Balb/c mice developed diarrhea, which was associated with increased number of mast cells and expression of interleukin (IL)-4 and -13, and chemokines CCL1 and CCL17 in the small intestine. Treatment with imatinib reduced the incidence of diarrhea, inhibited the development of mastocytosis and jejunal mRNA expression of IL-13, CCL1, CCL17 and CCL22. Mast cell-deficient W/W(-V) mice, and surprisingly, also their mast cell-competent control (+/+) littermates failed to develop diarrhea as a response to ovalbumin. This strain-dependent difference was associated with the inability of +/+ and W/W(-V) mice to increase the number of intestinal mast cells and expression of IL-4, IL-13, CCL1 and CCL17 after ovalbumin challenge.


CONCLUSIONS
Development of allergic diarrhea is associated with the ability of mice to develop intestinal mastocytosis. Imatinib inhibited the development of intestinal mastocytosis, reduced the incidence of diarrhea, and reduced the expression of IL-13, CCL1, and CCL17. Targeting intestinal mast cells could be a feasible approach to treat allergic diarrhea.
Institute of Medicine, University of Bergen, Norway. kirsi.vaali@med.uib.no
K
K
Vaali
J
J
Lappalainen
A H
AH
Lin
M I
MI
Mäyränpää
P T
PT
Kovanen
A
A
Berstad
K K
KK
Eklund
D000485:Allergens / Q000276:immunology; D000818:Animals; D001549:Benzamides; D003967:Diarrhea / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D005512:Food Hypersensitivity / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D000068877:Imatinib Mesylate; D007422:Intestines / Q000187:drug effects / Q000276:immunology; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000485:Allergens; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D010047:Ovalbumin