Activin-A causes Hepatic stellate cell activation via the induction of TNFα and TGFβ in Kupffer cells

Abstract

Activin-A may induce fibrosis in NASH and alcoholic cirrhosis via activation of KCs to express pro-inflammatory molecules that promote HSC-dependent fibrogenesis and could be a target for future anti-fibrotic therapies.

Role of cytokines in pathogenesis and progression of nonalcoholic steatohepatitis

“…A number of intraand extracellular inhibitors, including follistatin and follistatin-related proteins that bind and disable activin-A, coordinate its effects. [31][32][33][34][35] One well established effects of activin-A is it´s role in the wound cure and fracture consolidation. Deregulation of this process is related to pathological collagen accumulation.…”

“…Studies in animal models and small series of patients suggest that activin-A system can participate in inflammation and liver fibrosis. 20,[31][32][33][34] Oxidative stress is also responsible for production of proinflammatory cytokines, among which stand out: TNF-α, transforming growth factor alpha and beta (TGF-α and TGF-β), interleukin-6 (IL-6), interleukin-8 (IL-8), NFκB and adiponectin. These cytokines are produced by lymphocytes and Kupffer cells, mediated by free radicals and it may act by changing the mitochondrial membrane permeability and inhibiting the respiratory chain 35 .…”

“…TNFR1 signaling disruption upon a HFD leads to an accelerated progression from simple steatosis towards a more severe phenotype with many NASH features, pointing out a key role of TNFR1 in NAFLD progression. 13,14,19,31,[33][34][35][36] Ghrelin is a peptide hormone that was discovered in 1999, and acts as a growth hormone receptor binder (GHS-R) with a single posttranslational modification of the residue Ser, it´s produced in stomach, pancreas and large intestine. Grelin has part in stimulating appetite and controlling body mass.…”

Fagonia indica Repairs Hepatic Damage through Expression Regulation of Toll-Like Receptors in a Liver Injury Model

“…Activated HSCs secrete an extracellular matrix, mainly collagen I, III, and IV [ 71 , 72 ]. Overall, induction of TNF- α and TGF- β in Kupffer cells leads to HSC activation resulting in an upregulation of fibrosis markers α -SMA and col-1 α [ 73 ]. Studies have reported reversal of liver injury via regulation of proinflammatory genes by medicinal plants such as Aspalathus linearis [ 68 ] and Cynara scolymus L. [ 74 ].…”

Inositol-Requiring Enzyme 1 Alpha Endoribonuclease Specific Inhibitor STF-083010 Alleviates Carbon Tetrachloride Induced Liver Injury and Liver Fibrosis in Mice

“…In fact, the studies showed that α-SMA was a marker of the initiation stage of HSCs activation, which was evidently raised in the liver region of bridging fibrosis, and the mRNA levels of hepatic col1α1 and col1α2, markers for the perpetuation stage of HSCs activation, were clearly elevated in fibrotic mice ( Osterreicher et al, 2009 ; Wang et al, 2013 ; Heindryckx et al, 2016 ). Several reports demonstrated that inflammatory cytokines such as MCP1, IL-1β, IL-6, and TGF-β1 were closely related to the activation of HSCs ( Moles et al, 2014 ; Wu et al, 2015 ; Kim et al, 2017 ; Kiagiadaki et al, 2018 ). It was reported that pre-treatment with IRE1α inhibitor reduced pro-inflammatory cytokines production in tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) dermal fibroblasts (DFs) ( Harrison et al, 2018 ).…”