A ROLE FOR STEM-CELL FACTOR AND C-KIT IN THE MURINE INTESTINAL-TRACT SECRETORY RESPONSE TO CHOLERA-TOXIN

The role of stem cell factor (SCF) and its receptor (c-kit) in the int estinal secretory response to cholera toxin (CT) was investigated usin g a ligated intestinal loop model in mice having mutations in the domi nant white spotting (W) locus and the steel (Sl) locus. W/W-V mice, wh ich express an aberrant form of the c-kit protein, failed to give an i ntestinal secretory response after luminal CT challenge. In contrast, W/W-V mice and their control littermates had equivalent intestinal sec retory responses to Escherichia coli heat-stable enterotoxin (STa). Sl /Sl(d) mice, which express only a soluble truncated form of SCF, also gave a significantly reduced intestinal secretory response to CT when compared to the secretory response of their littermate controls. The u nresponsiveness of W/W-V mice to CT was restricted to the intestinal t ract since these mice had foot pad swelling responses to CT challenge that were equivalent to their littermate controls. Restoration of mast cells in W/W-V mice by bone marrow transplantation of control litterm ate bone mat-row did not reverse the CT-unresponsiveness oi the intest inal tract. Histological evaluation of the gastrointestinal tract from W/W-V mice showed a normal distribution of enterochromaffin cells (EC C). CT challenge of either ligated intestinal loops from C57Bl/6 mice or a mouse intestinal epithelial cell line (MODE-K) resulted in elevat ed levels of mRNA for SCF. MODE-K cells exposed to CT also had enhance d expression of c-kit. Finally, fluid obtained from CT-challenged liga ted intestinal loops from C57Bl/6 mice contained significant levels of SCF. Taken together, the above results suggest that CT-induced intest inal secretory responses are dependent upon SCF-c-kit interactions. Th ese interactions appear to be induced as a consequence of CT stimulati on of the intestinal tract and may also play a role in the development or functionality of the enteric nervous system.