Kupffer-cell-expressed transmembrane TNF-[alpha] is a major contributor to lipopolysaccharide and D-galactosamine-induced liver injury

• Published in: Cell and tissue research Vol. 363; no. 2; p. 371
• Main Authors: Yang, Peng, Zhou, Wenjing, Li, Chenxi, Zhang, Meng, Jiang, Yaping, Jiang, Rui, Ba, Hongping, Li, Cheng, Wang, Jing, Yin, Bingjiao, Gong, Feili, Li, Zhuoya
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.02.2016; Springer Nature B.V
• Subjects: Analysis; Apoptosis; Biological activity; Cytokines; Hepatitis; Liver; Liver diseases; Mitogens; Tumor necrosis factor; Tumor necrosis factor-TNF
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-015-2252-2

Tumor necrosis factor (TNF)-[alpha] exists in two bioactive forms, a 26-kDa transmembrane form (tmTNF-[alpha]) and a 17-kDa soluble form (sTNF-[alpha]). sTNF-[alpha] has been recognized as a key regulator of hepatitis; however, serum sTNF-[alpha] disappears in mice during the development of severe liver injury, and high levels of serum sTNF-[alpha] do not necessarily result in liver damage. Interestingly, in a mouse model of acute hepatitis, we have found that tmTNF-[alpha] expression on Kupffer cells (KCs) significantly increases when mice develop severe liver injury caused by lipopolysaccharide (LPS)/D-galactosamine (D-gal), and the level of tmTNF-[alpha] expression is positively related to the activity of serum transaminases. Therefore, we hypothesized that KC-expressed tmTNF-[alpha] constitutes a pathomechanism in hepatitis and have explored the role of tmTNF-[alpha] in this disease model. Here, we have compared the impact of KCs.sup.tmTNFlow and KCs.sup.tmTNFhigh on acute hepatitis in vivo and ex vivo and have further demonstrated that KCs.sup.tmTNFhigh, rather than KCs.sup.tmTNFlow, not only exhibit an imbalance in secretion of pro- and anti-inflammatory cytokines, favoring inflammatory response and exacerbating liver injury, but also induce hepatocellular apoptosis via tmTNF-[alpha] and the expression of another pro-apoptotic factor, Fas ligand. Our data suggest that KC.sup.tmTNFhigh is a major contributor to liver injury in LPS/D-gal-induced hepatitis.