Magnolol Attenuates Concanavalin A‐induced Hepatic Fibrosis, Inhibits CD4⁺ T Helper 17 (Th17) Cell Differentiation and Suppresses Hepatic Stellate Cell Activation: Blockade of Smad3/Smad4 Signalling

Abstract

Magnolol is a pharmacological biphenolic compound extracted from Chinese herb Magnolia officinalis, which displays anti-inflammatory and antioxidant effects. This study was aimed at exploring the potential effect of magnolol on immune-related liver fibrosis. Herein, BALB/c mice were injected with concanavalin A (ConA, 8 mg/kg/week) up to 6 weeks to establish hepatic fibrosis, and magnolol (10, 20, 30 mg/kg/day) was given to these mice orally throughout the whole experiment. We found that magnolol preserved liver function and attenuated liver fibrotic injury in vivo. In response to ConA stimulation, the CD4 T cells preferred to polarizing towards CD4 T helper 17 (Th17) cells in liver. Magnolol was observed to inhibit Th17 cell differentiation in ConA-treated liver in addition to suppressing interleukin (IL)-17A generation. Hepatic stellate cells were activated in fibrotic liver as demonstrated by increased alpha smooth muscle actin (α-SMA) and desmin. More transforming growth factor (TGF)-β1 and activin A were secreted into the serum. Magnolol suppressed this abnormal HSC activation. Furthermore, the phosphorylation of Smad3 in its linker area (Thr179, Ser 204/208/213) was inhibited by magnolol. In vitro, the recombinant IL-17A plus TGF-β1 or activin A induced activation of human LX2 HSCs and promoted their collagen production. Smad3/Smad4 signalling pathway was activated in LX2 cells exposed to the fibrotic stimuli, as illustrated by the up-regulated phospho-Smad3 and the enhanced interaction between Smad3 and Smad4. These alterations were suppressed by magnolol. Collectively, our study reveals a novel antifibrotic effect of magnolol on Th17 cell-mediated fibrosis.

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

“…Of note, the AIMP1 peptide did not influence TGF-β-induced phosphorylation of SMAD2 and SMAD3 but inhibited the nuclear translocation of SMAD3 by a still not identified mechanism [264]. Moreover, Zhang and his colleagues used magnolol to prevent the interaction between SMAD3 and SMAD4 and, thus, could attenuate TGF-β signaling and concanavalin A induced hepatic fibrosis [265]. In line with the above description on the distinct roles of SMAD3 and SMAD2 in organ fibrosis, a recent study reported the efficacy of a specific SMAD3 inhibitor (SIS3) in reducing fibrosis, apoptosis, and inflammation in a mouse model of kidney fibrosis [266], however, a therapeutic effect of SIS3 on liver fibrosis still remains poorly defined.…”

The Roles of Immune Cells in the Pathogenesis of Fibrosis

“…IL-17 signaling facilitated the production of multiple cytokines including TGF-β, and directly induced production of collagen in HSCs through activation of signal transducers and activators of transcription (STAT) 3 signaling pathway [ 91 ]. Inhibition of Th17 cells by small molecules Halofugine and Magnolol significantly reduced the severity of Concanavalin A-induced liver fibrosis, suggesting that Th17 cells may represent novel therapeutic targets for treating liver fibrosis [ 92 , 93 ].…”

A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids

“…In vitro research showed that 12.5–50 μ mol/L honokiol induced apoptotic death in activated rat HSCs through the release of mitochondrial cytochrome C [ 140 ]. Magnolol also attenuated ConA-induced liver fibrosis and suppressed human LX2 HSC activation, which was closely related to inhibiting Th17 cell differentiation by suppressing IL-17A generation [ 141 ]. In addition, other honokiol derivatives, such as 4′-O-methylhonokiol, also prevented from HSC activation and induced apoptosis via regulation of Bak1 and Bcl-2 expression [ 142 ].…”