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(American Journal of Pathology. 2006;169:861-876.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050767

A Role for Serotonin (5-HT) in Hepatic Stellate Cell Function and Liver Fibrosis

Richard G. Ruddell^*, Fiona Oakley^*, Ziafat Hussain^*, Irene Yeung^*, Lesley J. Bryan-Lluka, Grant A. Ramm and Derek A. Mann^*

From the Liver Group,^* Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom; the Hepatic Fibrosis Group, Queensland Institute of Medical Research, Herston, Queensland, Australia; and the School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia

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-HT_1B, 5-HT_1F 5-HT_2A 5-HT_2B, and 5-HT₇ receptors, with expression of 5-HT_1B 5-HT_2A and 5-HT_2B being induced on HSC activation. Induction of 5-HT_2A and 5-HT_2B was 106 ± 39- and 52 ± 8.5-fold that of quiescent cells, respectively. 5-HT_2B 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.

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