Tuberous sclerosis (TS) is characterized by the development of hamartomas in various organs and is caused by a germ-line mutation in either TSC1 or TSC2 tumor suppressor genes. From the symptomatic resemblance among TS patients, involvement of TSC1 and TSC2 products in a common pathway has been suggested. Here, to analyze the function of the Tsc1 product, we established a line of Tsc1 (TSC1 homologue) knockout mouse by gene targeting. Heterozygous Tsc1 mutant (Tsc1 ؉/؊ ) mice developed renal and extra-renal tumors such as hepatic hemangiomas. In these tumors, loss of wild-type Tsc1 allele was observed. Homozygous Tsc1 mutants died around embryonic days 10.5-11.5, frequently associated with neural tube unclosure. As a whole, phenotypes of Tsc1 knockout mice resembled those of Tsc2 knockout mice previously reported, suggesting that the presumptive common pathway for Tsc1 and Tsc2 products may also exist in mice. Notably, however, development of renal tumors in Tsc1 ؉/؊ mice was apparently slower than that in Tsc2 ؉/؊ mice. The Tsc1 knockout mouse described here will be a useful model to elucidate the function of Tsc1 and Tsc2 products as well as pathogenesis of TS.T uberous sclerosis (TS) is an autosomal dominantly inherited disease characterized by the development of hamartomas and benign tumors in various organs such as brain, kidney, and heart (1). A germ-line mutation in either TSC1 or TSC2 genes (2, 3), both of which act as tumor suppressors (4, 5), is a genetic factor responsible for pathogenesis of TS. The similar symptoms of TS patients associated with TSC1 or TSC2 mutations suggest that the products of TSC1 and TSC2 are involved in a common physiological pathway (1, 6). TSC1 encodes a protein with a molecular mass of Ϸ130 kDa, hamartin, which contains a coiled-coil domain in the carboxyl-terminal half (3). TSC2 encodes tuberin, a rap1-GTPase activating protein homology domain-containing protein with a molecular mass of Ϸ180 kDa (2). Although several studies concerned with functions of these products have been reported, in vivo functions of them remain to be elucidated (1,7,8).The tumor suppressor function of TSC2 became evident by studies of rodents with a germ-line Tsc2 mutation such as the Eker rat (9-13) and Tsc2 knockout mice (14, 15). Both heterozygous Tsc2 mutant rats and mice develop hereditary renal tumors and extra-renal tumors carrying a second hit of Tsc2 gene (14-17). Homozygosity of Tsc2 mutation leads to the embryonic lethality both in rats (9, 18) and mice (15,16), indicating that the function of tuberin is essential for mammalian development.We also isolated a rat homologue of TSC1 (Tsc1) and analyzed its mutation in chemically induced renal tumors in wild-type rats, in which Tsc2 mutations were found with high frequency (Ϸ50%) (19). In those tumors, we found Tsc1 mutations in a case with no Tsc2 mutation (19). These results suggest that mutations of Tsc1 and Tsc2 are involved in the development of chemically induced renal tumors in rats, although the latter is more common. These systems o...

No abstract

Summary. Peripheral blood monocytes are common precursor cells of dendritic cells (DCs) and macrophages. We have searched for factors with the potential to regulate the differentiation of monocytes to DCs and macrophages. When CD141 monocytes are cultured with granulocyte± macrophage colony-stimulating factor (GM-CSF) and interleukin (IL) 4, the CD14 1 CD1a 2 population, which consists of macrophages, was found in the serum-containing cultures but not in the serum-free cultures. Addition of IL-6 receptor-neutralizing monoclonal antibody (mAb) or gp130-neutralizing mAb to the serum-containing cultures resulted in a decreased population of CD141 CD1a 2 cells. An increase in the CD141 CD1a 2 population with reduction in CD14 2 CD1a 1 DCs was observed with the addition of IL-6 to cultures, whereas IL-11, leukaemia inhibitory factor, oncostatin M or macrophage colony-stimulating factor did not affect the differentiation of monocytes in the presence of GM-CSF plus IL-4. This effect of IL-6 was blocked by tumour necrosis factor a (TNF-a), lipopolysaccharide (LPS), IL-1b, CD40 ligand (CD40L) and transforming growth factor b1 (TGF-b1). Among these factors, TNF-a was most potent in interfering with the action of IL-6. These results suggest that IL-6 inhibits the differentiation of monocytes to DCs by promoting their differentiation toward macrophages, which is modulated by factors such as TNF-a, LPS, IL-1b, CD40L and TGF-b1.