Interactions between stromal cell--derived keratinocyte growth factor and epithelial transforming growth factor in immune-mediated crypt cell hyperplasia.

Abstract

Immune reactions in the gut are associated with increased epithelial cell proliferation. Here we have studied the role of keratinocyte growth factor (KGF; FGF7) and transforming growth factor-␣ (TGF-␣ ) in the epithelial cell hyperplasia seen in explants of fetal human small intestine after activation of lamina propria T cells with the superantigen Staphylococcus aureus enterotoxin B (SEB). After the addition of SEB 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. SEB had no direct effect on KGF mRNA and protein production by cultured lamina propria mesenchymal cells, but both were upregulated by TNF-␣ . Accompanying the increase in KGF there was also an increase in TGF-␣ precursor proteins in the culture supernatants and the phosphorylated form of the EGFR receptor was also detected in the tissue. Increased TGF-␣ precursor proteins were also detected in the supernatants of control explants stimulated with KGF alone. The direct addition of KGF and TGF-␣ enhanced epithelial cell proliferation and antibodies against KGF and TGF-␣ partially inhibited SEB-induced crypt hyperplasia. These results suggest molecular cross-talk between the KGF/KGFR and the TGF-␣ /EGFR in immunemediated crypt cell hyperplasia. ( J. Clin. Invest. 1998. 102: 1473-1480.)

Intestinal Intraepithelial Lymphocyte γδ-T Cell-Derived Keratinocyte Growth Factor Modulates Epithelial Growth in the Mouse

“…It was interesting to note that KGF expression increased within a week after the development of SBS, suggesting it was an important early regulator of villus hypertrophy. As shown in our results, ␥␦-TCR Ϫ/Ϫ mice do not express mucosal KGF; however, lamina propria-derived KGF (from nonlymphoid cells) is still present (7,34). Use of ␥␦-TCR Ϫ/Ϫ mice has given us insight into the physiologic relevance of IEL-derived KGF on normal villus growth, and how it affects adaptive changes with TPN or in SBS.…”

“…KGF expression appears critical to fetal development of the human intestinal epithelium (15,34,40). KGF mRNA expression has been shown to increase in inflammatory bowel disease and in a starvation mouse model (16,19,41,42).…”

“…This finding of a decline in villus height corresponds to the findings of Komano et al (35), who found a decline in both epithelial proliferation and turnover in ␥␦ Ϫ/Ϫ mice. Clearly, the production of KGF from stromal cells of the lamina propria is present, and still must function to some degree to support epithelial growth through a paracrine action (6,17,34). It has been shown that stromal cells in the lamina propria have a strong role in epithelial proliferation (34).…”

Recent Developments in the Immunology of Inflammatory Bowel Disease

“…KGF is a good candidate for a molecule which can link immune reactions in the lamina propria with epithelial proliferation because its receptor, a splice variant of FGFRII, is expressed only on epithelial cells. KGF is overexpressed in active IBD stromal cells [65][66][67] and functional studies in the foetal gut model described above indicate that it is also upregulated in explants following T-cell activation with bacterial superantigens, coincident with crypt hyperplasia [68]. Inhibition of KGF in this model decreases T cell mediated crypt hyperplasia.…”

Inmunología de la enfermedad celíaca

“…En la EC activa los linfocitos T CD4 þ de la lámina propia y los LIE CD8 þ contribuyen a desencadenar una respuesta Th1 dominada por el IFN-g, el factor de transcripción T-bet y otras citocinas proinflamatorias (TNF-a, IL18, IL21), junto a un descenso de IL10 e TGFb [37][38][39] , y la producción de IL15 por los enterocitos 5 . Este perfil de tipo proinflamatorio, que desaparece en los pacientes en remisión, activa mecanismos efectores del daño tisular, en los que interviene el factor de crecimiento de queratinocitos 40 , y metaloproteinasas de matriz 41,42 , implicados en la degradación de la matriz extracelular y la transformación mucosa.…”