INTERACTIONS BETWEEN STROMAL CELL-DERIVED KERATINOCYTE GROWTH-FACTOR AND EPITHELIAL TRANSFORMING-GROWTH-FACTOR IN IMMUNE-MEDIATED CRYPT CELL HYPERPLASIA

Immune reactions in the gut are associated with increased epithelial c ell proliferation. Here we have studied the role of keratinocyte growt h factor (KGF; FGF7) and transforming growth factor-alpha (TGF-alpha) in the epithelial cell hyperplasia seen in explants of fetal human sma ll intestine after activation of lamina propria T cells with the super antigen Staphylococcus aureus enterotoxin B (SEB). After the addition of SEE to the explants there is a 10-fold increase in KGF mRNA by 72 h of culture. KGF transcripts were abundant in the lamina propria using in situ hybridization and the culture supernatants contained elevated amounts of KGF protein. SEE had no direct effect on KGF mRNA and prot ein production by cultured lamina propria mesenchymal cells, but both were upregulated by TNF-alpha. Accompanying the increase in KGF there was also an increase in TGF-alpha precursor proteins in the culture su pernatants and the phosphorylated form of the EGFR receptor was also d etected in the tissue. Increased TGF-alpha precursor proteins were als o detected in the supernatants of control explants stimulated with KGF alone. The direct addition of KGF and TGF-alpha enhanced epithelial c ell proliferation and antibodies against KGF and TGF-alpha partially i nhibited SEE-induced crypt hyperplasia. These results suggest molecula r cross-talk between the KGF/KGFR and the TGF-alpha/EGFR in immune-med iated crypt cell hyperplasia.