Characterization of integrin ?6 and thrombospondin-1 double-null mice

Abstract

To identify overlapping and non‐overlapping functions for TSP‐1 and αvβ6, we crossed TSP‐1‐null and β6‐null mice and compared the phenotype of the double‐null mice with those of wild‐type and single‐null mice. The double‐null mice exhibited focal acute and organizing pneumonia that was more severe than the wild‐type and single‐null mice as well as a significantly higher incidence of inflammation in tissues other than the lung. The TSP‐1‐null and β6‐null mice exhibited a five to eight‐fold increase in granulocyte recruitment to the lung three days after exposure to lipopolysaacharide. They also had abnormalities that were infrequently observed in the wild‐type and single‐null mice, including heart degeneration (8.35% in wild‐type and 28.1% in double‐null mice), hyperplasia of the glandular epithelium of the stomach (2.8% in wild‐type and 21.1% in double‐null mice) and endometrial hyperplasia (0% in wild‐type and 38.5% in double‐null females). Furthermore, the β6‐null and double‐null mice displayed a significant elevation in benign and malignant cancers. Stomach papillomas, squamous cell carcinomas of the ear and stomach, and adenocarcinomas of the lungs, vagina/cervix and colon were observed with the highest frequency. These data demonstrate that TSP‐1 and αvβ6 are involved in regulation of the immune system and epithelial homeostasis. They also indicate that αvβ6 functions as a tumor suppressor gene and that activation of TGFβ by TSP‐1 and αvβ6 contributes to normal tissue architecture and function.