Back to Search
Start Over
Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells.
- Source :
-
American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2006 Nov; Vol. 291 (5), pp. G877-84. Date of Electronic Publication: 2006 Jun 15. - Publication Year :
- 2006
-
Abstract
- Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through alpha1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-alpha1(I) expression were assessed by [3H]thymidine incorporation and quantitative PCR, respectively. NF-kappaB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed alpha(1A)-adrenoceptors, which were markedly upregulated in livers with advanced fibrosis. Activated human HSC expressed alpha(1A)-adrenoceptors. NE induced multiple rapid [Ca2+]i oscillations (Ca2+ spikes). Prazosin (alpha1-blocker) completely prevented NE-induced Ca2+ spikes, whereas propranolol (nonspecific beta-blocker) partially attenuated this effect. NE caused phosphorylation of MLC II and cell contraction. In contrast, NE did not affect cell proliferation or collagen-alpha1(I) expression. Importantly, NE stimulated the secretion of inflammatory chemokines (RANTES and interleukin-8) in a dose-dependent manner. Prazosin blocked NE-induced chemokine secretion. NE stimulated NF-kappaB activation. BAY 11-7082, a specific NF-kappaB inhibitor, blocked NE-induced chemokine secretion. We conclude that NE stimulates NF-kappaB and induces cell contraction and proinflammatory effects in human HSC. Catecholamines may participate in the pathogenesis of portal hypertension and liver fibrosis by targeting HSC.
- Subjects :
- Adenoviridae genetics
Blotting, Western
Cell Proliferation drug effects
Chemokines biosynthesis
Collagen biosynthesis
Electrophoretic Mobility Shift Assay
Gene Expression Regulation drug effects
Glyceraldehyde-3-Phosphate Dehydrogenases genetics
Glyceraldehyde-3-Phosphate Dehydrogenases metabolism
Humans
Inflammation chemically induced
Liver cytology
Liver drug effects
Liver Cirrhosis metabolism
Liver Cirrhosis pathology
NF-kappa B metabolism
RNA biosynthesis
RNA genetics
Receptors, Adrenergic genetics
Receptors, Adrenergic metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transfection
Up-Regulation
Calcium Signaling drug effects
Inflammation metabolism
Liver metabolism
Norepinephrine pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0193-1857
- Volume :
- 291
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Publication Type :
- Academic Journal
- Accession number :
- 16782692
- Full Text :
- https://doi.org/10.1152/ajpgi.00537.2005