Blocking ICOS in combination with CD28 impairs the proper activation of aggressor Th1 cells but is not necessary for suppression by regulatory T cells

Abstract

<h2>Abstract</h2> <b>Background & Aims:</b> Hepatic stellate cell (HSC) transformation and proliferation play an important role in liver fibrogenesis, and HSC apoptosis may be involved in the termination of this response. <b>Methods:</b> Expression of the peripheral benzodiazepine receptor (PBR) and PBR-ligand–induced apoptosis were studied in cultured rat liver HSC. <b>Results:</b> Transformation of HSC led to a transient expression of PBR at the messenger RNA and protein level, which was maximal after about 3 and 7 days of culture, respectively, and declined thereafter. Immunoreactive PBR showed a punctate staining and colocalized with mitochondrial manganese-dependent superoxide dismutase and adenine nucleotide translocator 1. The selective PBR ligands 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195) and 4' chlorodiazepam (Ro5-4864), but not the centrally acting benzodiazepine ligand clonazepam, induced dose-dependent apoptosis in HSC. The apoptotic potency of PK11195 paralleled the level of PBR expression. PK11195 induced dephosphorylation of protein kinase B/Akt and Bad and a downregulation of Bcl-2. Collapse of the mitochondrial membrane potential preceeded PBR-ligand–induced apoptosis. No apoptosis was induced by PK11195 in parenchymal cells, despite the presence of PBR, and PK11195 had no effect in these cells on Bad phosphorylation and Bcl-2 expression. <b>Conclusions:</b> Transformation of HSC leads to a transient expression of PBR and renders the cells sensitive to PBR-ligand–induced apoptosis, involving protein kinase B/Akt and Bad-dependent mechanisms. GASTROENTEROLOGY 2001;120:1212-1226