T Bushnell | PubMed Health

PubMed2001

Hamartin and tuberin expression in human tissues.

Tuberous sclerosis (TSC) is a bigenic autosomal dominant disease caused by mutations in one of two tumor-suppressor genes, TSC1 and TSC2, resulting in benign hamartomas and low grade neoplasms in multiple organs including brain, heart, kidney, and skin. We report the results of an immunohistochemical study of the expression of the TSC gene products, tuberin and hamartin, in multiple tissues obtained at autopsy from 12 non-TSC affected patients ranging in age from 20 weeks gestation to 8 years, and surgical specimens from some organs. Tuberin and hamartin are expressed and are colocalized in most tissues. Contrary to a previous report, immunostaining with our antisera detected hamartin in liver, small and large intestine, prostate, and testes. We did not detect significant developmental differences in tuberin or hamartin expression in comparable tissues from patients of different ages. Although tuberin and hamartin colocalize in most tissues and cell types, we provide data that hamartin is more abundantly expressed than tuberin in cells within some tissues including the distal nephron and a population of cells of the endocrine pancreas. These data support the hypothesis that hamartin and tuberin interact and may function together in many tissues where they are co-expressed, but also suggest that hamartin has a discrete and specialized function in certain cell types.

Blotting, Western↗

PubMed2001

Tetracyclines inhibit activated B cell function.

Tetracyclines have recently been shown to exert a number of pleiotropic anti-inflammatory and immunomodulatory activities, independent of their antibiotic properties. These include the ability to inhibit metalloproteinases (MP), a class of enzymes involved in crucial cellular functions such as the shedding of soluble mediators and their receptors from the cell surface, as well as interaction with, and remodeling of, the extracellular matrix. Here we report that doxycycline at therapeutic concentrations (1--5 microg/ml) significantly suppresses Ig secretion and class switching by in vitro activated murine B cells. Suppression of Ig secretion correlates with a decrease in levels of mRNA for the terminal B cell differentiation-associated genes Blimp-1 and mad-4, as well as to a reduction in expression of the plasma cell markers Syndecan-1 and J chain. Inhibition of class switching occurs at the recombination stage and is also induced by other MP inhibitors, including tetracycline analogs lacking antibiotic activity and the chemically unrelated hydroxamate KB8301. These novel, direct effects of MP inhibitors on B lymphocytes suggest an intrinsic role for MP in B cell activation and likely explain some of the observed in vivo immunomodulatory properties of tetracyclines. Moreover, these findings have significant implications for tetracycline therapy in Ig-mediated autoimmune or allergic diseases and raise questions about the use of doxycycline-inducible transgenic systems for the study of B cell function.

Animals↗