Abstract
Janus kinase 3 (Jak3) is a non-receptor tyrosine kinase known to be expressed in hematopoietic cells. Studies of whole organ homogenates show that Jak3 is also expressed in the intestines of both human and mice. However, neither its expression nor its function has been defined in intestinal epithelial enterocytes. The present studies demonstrate that functional Jak3 is expressed in human intestinal enterocytes HT-29 Cl-19A and Caco-2 and plays an essential role in the intestinal epithelial wound repair process in response to interleukin 2 (IL-2). Exogenous IL-2 enhanced the wound repair of intestinal enterocytes in a dose-dependent manner. Activation by IL-2 led to rapid tyrosine phosphorylation and redistribution of Jak3. IL-2-stimulated redistribution of Jak3 was inhibited by the Jak3-specific inhibitor WHI-P131. IL-2 also induced Jak3-dependent redistribution of the actin cytoskeleton in migrating cells. In these cells Jak3 interacted with the intestinal and renal epithelial cell-specific cytoskeletal protein villin in an IL-2-dependent manner. Inhibition of Jak3 activation resulted in loss of tyrosine phosphorylation of villin and a significant decrease in wound repair of the intestinal epithelial cells. Previously, we had shown that tyrosine phosphorylation of villin is important for cytoskeletal remodeling and cell migration. The present study demonstrates a novel pathway in intestinal enterocytes in which IL-2 enhances intestinal wound repair through mechanisms involving Jak3 and its interactions with villin.
Highlights
Epithelial cells in the gastrointestinal mucosa play an important role in defining the physical barrier between the host and the external environment
interleukin 2 (IL-2) Promotes Wound Closure in intestinal epithelial cells (IEC)—Because IL-2 was found to be important in experimental models of colitis [6] and in human colitis patients [7], we investigated whether IL-2 stimulates IEC migration in vitro using a scratch wound assay
The IL-2-stimulated increase in wound closure was diminished by both inhibitors to the same extent, suggesting that IL-2-induced wound closure in intestinal epithelial cells is mediated by Janus kinase 3 (Jak3) activation
Summary
Janus Kinase 3 Regulates Interleukin 2-induced Mucosal Wound Repair through Tyrosine Phosphorylation of Villin*□S. The present studies demonstrate that functional Jak is expressed in human intestinal enterocytes HT-29 Cl-19A and Caco-2 and plays an essential role in the intestinal epithelial wound repair process in response to interleukin 2 (IL-2). Previous studies with IL-2R␥- and Jak3-null mice showed that both of these strains developed spontaneous inflammatory bowel disease symptoms including damaged intestinal mucosa [10] This suggests that both proteins may be important for intestinal wound repair, but the role of Jak has not been investigated previously in intestinal epithelial repair mechanisms. We demonstrate that intestinal epithelial cells express functionally specific Jak, a potent non-receptor tyrosine kinase whose biological functions have been presumed to be largely limited to lymphocyte and macrophage populations [8], and propose a mechanism through which activated Jak and villin regulate intestinal epithelial wound repair
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