Depletion of serotonin relieves concanavalin A-induced liver fibrosis in mice by inhibiting inflammation, oxidative stress, and TGF-β1/Smads signaling pathway.

Abstract

Serotonin exerts important functions in several liver pathophysiological processes. In this study, we investigated the role of serotonin in concanavalin A (Con A)-induced liver fibrosis (LF) in mice and the underlying mechanisms. To establish the mouse model of LF, mice of wild-type (WT) and tryptophan hydroxylase 1 (Tph1) knockout (serotonin depletion) received Con A for 8 successive weeks. Degree of fibrosis was assessed by Sirius red staining, as well as the measurements of alpha smooth muscle actin (α- SMA), hydroxyproline (Hyp) and type I collagen in liver tissues. To elucidate the potential mechanisms, we assessed the effect of serotonin depletion on inflammatory, oxidative stress as well as TGF-β1/Smads signaling pathway. We found that serotonin depletion significantly inhibited collagen deposition as evaluated by less collagenous fiber in Sirus Red staining and reduced contents of Hyp and type I collagen. In addition, the absence of serotonin significantly inhibited the release of several inflammatory cytokines, including interleukin-6 (IL-6), interferon-gamma (IFN-γ), tumor necrosis-alpha (TNF-α), and transforming growth factor β1 (TGF-β1). Oxidative stress was also largely mitigated in LF mice with serotonin deficiency as manifested by the decreases of oxidative stress markers (malonaldehyde (MDA) and myeloperoxidase (MPO)), as well as the increases of antioxidant stress indicators (glutathione (GSH), and GSH-px, catalase (CAT), superoxide dismutase (SOD)) in liver tissues. Moreover, the lack of serotonin may provide an antifibrotic role by inhibiting the intrahepatic expressions of TGF-β1, phosphorylated-smad2 (p-smad2), and phosphorylated-smad3 (p-smad3). These results indicated that, serotonin depletion attenuates Con A-induced LF through the regulation of inflammatory response, oxidative stress injury, and TGF-β1/Smads signaling pathway.

• Authors: Qing Pang, Hao Jin, Yong Wang, Mengnan Dai, Shuangchi Liu, Yi Tan, Huichun Liu, Zheng Lu
• Journal: Toxicology letters (Toxicol Lett) Vol. 340 Pg. 123-132 (Apr 01 2021) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 33429011 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier B.V.

Chemical References

• Mitogens
• Smad Proteins
• Transforming Growth Factor beta1
• Concanavalin A
• Serotonin
• Tph1 protein, mouse
• Tryptophan Hydroxylase

Topics

• Animals
• Concanavalin A (administration & dosage, pharmacology)
• Humans
• Inflammation (chemically induced, prevention & control)
• Liver Cirrhosis (chemically induced)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogens (toxicity)
• Oxidative Stress (drug effects)
• Serotonin (pharmacology)
• Signal Transduction
• Smad Proteins (genetics, metabolism)
• Transforming Growth Factor beta1 (genetics, metabolism)
• Tryptophan Hydroxylase (genetics, metabolism)