Cytokine-mediated up-regulation of CD55 and CD59 protects human hepatoma cells from complement attack

Abstract

SUMMARYHepatic parenchymal cells respond in many different ways to acute-phase cytokines. Some responses may protect against damage by liver-derived inflammatory mediators. Previous investigations have shown that cytokines cause increased secretion by hepatoma cells of soluble complement regulatory proteins, perhaps providing protection from complement attack. More important to cell protection are the membrane complement regulators. Here we examine, using flow cytometry and Northern blotting, the effects of different cytokines, singly or in combination, on expression of membrane-bound complement regulators by a hepatoma cell line. The combination of tumour necrosis factor-alpha, IL-1b, and IL-6 caused increased expression of CD55 (three-fold) and CD59 (two-fold) and decreased expression of CD46 at day 3 post-exposure. Interferon-gamma reduced expression of CD59 and strongly antagonized the up-regulatory effects on CD59 mediated by the other cytokines. Complement attack on antibody-sensitized hepatoma cells following a 3-day incubation with the optimum combination of acute-phase cytokines revealed increased resistance to complement-mediated lysis and decreased C3b deposition. During the acute-phase response there is an increased hepatic synthesis of the majority of complement effector proteins. Simultaneous up-regulation of expression of CD55 and CD59 may serve to protect hepatocytes from high local concentrations of complement generated during the acute-phase response.

NF-κB and Enhancer-binding CREB Protein Scaffolded by CREB-binding Protein (CBP)/p300 Proteins Regulate CD59 Protein Expression to Protect Cells from Complement Attack

“…Furthermore, chronic inflammation, especially when induced by pathogens, has been implicated in tumorigenesis, where many proinflammatory and pathogenic virulence factors are produced in local tumor sites (36). These factors, such as TNF-␣, IL-1␤, IL-6, IL-10, and LPS, in turn up-regulate CD59 expression, as demonstrated here and previously (37,38), thereby allowing nascent tumor cells or cancer stem cells to escape from complement surveillance (39,40). Moreover, CD59 also has diverse complement-independent roles, including anti-apoptotic (41) and tumor angiogenic functions (42).…”

The Protective Role of CD59 and Pathogenic Role of Complement in Hepatic Ischemia and Reperfusion Injury

“…In the present study, we have demonstrated that inhibition of CD59 function in vitro sensitizes hepatocyte cells to complement-mediated cytotoxicity (see Supplemental Figure S3 at http://ajp.amjpathol.org), a finding in accord with results reported by Halme et al 38 MAC also mediates apoptotic effect on cells. 38,39,54 Consistently, we have demonstrated that pretreatment to deplete complement protects hepatocytes against complement-mediated apoptotic effect. Moreover, we found that the potential effect of MAC on endothelial damage and platelet acti- A: Liver histopathology in H&E-stained liver sections was examined at original magnification of ϫ10 and ϫ40.…”

“…35,37 Cytotoxicity Assay Hep3B cells were used because this cell line has been demonstrated to highly express human CD59. 38 We followed the same protocol as described previously 38,39 to culture the cells and to perform complement-mediated cytotoxicity assay. Briefly, 10 5 cells were treated with anti-hCD59 antibody (Bric 229 clone) for 40 minutes.…”

Mouse Complement Receptor-Related Gene y/p65-Neutralized Tumor Vaccine Induces Antitumor Activity In Vivo

“…In humans, complement-regulatory proteins are overexpressed on many kinds of tumor cells and tumor cell lines, and their expression prevents homologous complement attack in vitro (11)(12)(13)(14)(15)(16). The ability of complement-regulatory proteins to protect tumor cells from complement, and the ability of anti-complement regulator neutralizing mAbs to sensitize tumor cells to complement have been extensively studied in vitro (17, 34 -38).…”