Abstract
The regulation of collagen gene expression was studied in culture-activated rat hepatic stellate cells, the fibrogenic effector cell involved in hepatic fibrogenesis. Treatment of cells with a 5-lipoxygenase-specific inhibitor caused a reduction in alphaI(I) collagen mRNA transcript abundance, which suggested that leukotriene production was involved in maintaining the activated cell's high level of collagen mRNA production. The underlying mechanism involved a decrease in collagen gene transcription. Suppression of gene transcription was localized to an nuclear factor-1 (NF-1) binding domain in the proximal promoter and an AP-2 binding domain adjacent to it. Gel retardation assays demonstrated that an increase in AP-2 binding adjacent to the NF-1 site was likely to be the transmodulator responsible for the suppression of the NF-1-dependent gene expression. The data suggest that post-translational alterations in AP-2 activity are responsible for this unappreciated mechanism of regulating the collagen gene.
Highlights
IntroductionFrom structure-function studies on all three ligands, it has been established that a conserved Glu residue in the first ␣-helices of granulocyte-macrophage colonystimulating factor (GM-CSF), interleukin 3 (IL-3), and interleukin 5 (IL-5) is important for high affinity binding and biological activity [7,8,9]
§ To whom reprint requests should be addressed: Div. of Human Immunology, Institute of Medical and Veterinary Science, Box 14 Rundle Mall Post Office, Adelaide, South Australia 5000, Australia
The receptor ␣-chains for granulocyte-macrophage colonystimulating factor (GM-CSF), interleukin 3 (IL-3) and interleukin 5 (IL-5), and c belong to the rapidly expanding cytokine receptor superfamily. Within this superfamily several subfamilies are emerging that are characterized by the sharing of a communal receptor subunit by multiple ligands. gp130 acts as an affinity converter and signal transducer for IL-6 [12, 13], IL-11 [14], oncostatin M [15], ciliary neurotrophic factor, leukemia inhibitory factor (LIF) [16], and cardiotrophin-1 [17]; the LIF receptor binds ciliary neurotrophic factor [18], cardiotrophin-1 [17], and oncostatin M in addition to LIF [19]; IL-2R supports affinity conversion and signaling of IL-2 and IL-15 [20]; IL-2R ␥ chain affinity converts IL-2 [21], IL-4 [22], IL-7 [23], IL-9 [24], and
Summary
From structure-function studies on all three ligands, it has been established that a conserved Glu residue in the first ␣-helices of GM-CSF, IL-3, and IL-5 is important for high affinity binding and biological activity [7,8,9] This residue is thought to represent a common motif involved in c interaction and suggests that, reciprocally, the three ligands may use a common binding determinant in c. This study shows for the first time that a single residue in a communal cytokine receptor chain is involved in binding multiple ligands These results may be applicable to other common receptor subunits whose predicted FЈ-GЈ loop is shown to contain hydrophobic residues analogous to Tyr421 in c. The identification of a single residue in c involved in multiple ligand binding and signaling illustrates the profound susceptibility of this region and raises the possibility that a single compound targeted to it could simultaneously interfere with the function of multiple ligands
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