A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis.
Hepatic stellate cells (HSCs) are key cellular components of hepatic wound healing and fibrosis. There is emerging evidence that the fibrogenic function of HSCs may be influenced by neurochemical and neurotrophic factors. This study addresses the potential for the serotonin (5-HT) system to influence HSC biology. Rat and human HSCs express the 5-HT1B, 5-HT1F 5-HT2A 5-HT2B, and 5-HT7 receptors, with expression of 5-HT1B 5-HT2A and 5-HT2B being induced on HSC activation. Induction of 5-HT2A and 5-HT2B was 106+/-39- and 52+/-8.5-fold that of quiescent cells, respectively. 5-HT2B was strongly associated with fibrotic tissue in diseased rat liver. Treatment of HSCs with 5-HT2 antagonists suppressed proliferation and elevated their rate of apoptosis; by contrast 5-HT was protective against nerve growth factor-induced apoptosis. 5-HT synergized with platelet-derived growth factor to stimulate increased HSC proliferation. HSCs were shown to express a functional serotonin transporter and to participate in both active uptake and release of 5-HT. We conclude that HSCs express key regulatory components of the 5-HT system enabling them to store and release 5-HT and to respond to the neurotransmitter in a profibrogenic manner. Antagonists that selectively target the 5-HT class of receptors may be exploited as antifibrotic drugs.
Ruddell
Richard G
RG
Liver Research Group, Divison of Infection, Inflammation and Repair, University of Southampton School of Medicine, and Southampton General Hospital, UK.
Oakley
Fiona
F
Hussain
Ziafat
Z
Yeung
Irene
I
Bryan-Lluka
Lesley J
LJ
Ramm
Grant A
GA
Mann
Derek A
DA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D008099:Liver / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020932:Nerve Growth Factor / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
D018377:Neurotransmitter Agents; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D020932:Nerve Growth Factor