Activin-A causes Hepatic stellate cell activation via the induction of TNF alpha and TGF beta in Kupffer cells

作者：Kiagiadaki Foteini; Kampa Marilena; Voumvouraki Argyro; Castanas Elias; Kouroumalis Elias; Notas George^*

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2018, 1864(3): 891-899.

DOI：10.1016/j.bbadis.2017.12.031

• Activin-A
• Follistatin
• Non-alcoholic steatohepatitis
• Alcoholic liver disease
• Cirrhosis

Background & aims: TGF beta superfamily member Activin-A is a multifunctional hormone/cytokine expressed in multiple tissues and cells, where it regulates cellular differentiation, proliferation, inflammation and tissue architecture. High activin-A levels have been reported in alcoholic cirrhosis and non-alcoholic steatohepatitis (NASH). Our aim was to identify the cell types involved in the fibrotic processes induced by activin-A in liver and verify the liver diseases that this molecule can be found increased.
Methods: We studied the effect of activin-A on mouse primary Kupffer cells (KCs) and Hepatic Stellate cells (HSCs) and the levels of activin-A and its inhibitor follistatin in the serum of patients from a large panel of liver diseases.
Results: Activin-A is expressed by mouse hepatocytes, HSCs and Liver Sinusoid Endothelial cells but not KCs. Each cell type expresses different activin receptor combinations. HSCs are unresponsive to activin-A due to downregulation/desensitization of type-II activin receptors, while KCs respond by increasing the expression/production of TNF alpha kappa alpha l TGF beta 1. In the presence of KCs or conditioned medium from activin-A treated KCs, HSCs switch to a profibrogenic phenotype, including increased collagen and alpha SMA expression and migratory capacity. Incubation of activin-A treated KC conditioned medium with antibodies against TNFa and TGF beta 1 partially blocks its capacity to activate HSCs. Only patients with alcoholic liver diseases and NASH cirrhosis have significantly higher activin-A levels and activin-A/follistatin ratio.
Conclusions: 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.

• 出版日期2018-3