A reexamination of the role of clusterin as a complement regulator

Clusterin is a highly conserved glycoprotein which has been proposed to pro tect host cells against complement-mediated cytolysis, We tested the hypoth esis that clusterin is a complement regulator using erythrocytes and cells which had been stably transfected with a membrane-anchored form of clusteri n as targets for complement-mediated cytolysis. Clusterin gave dose-depende nt protection of antibody-coated sheep erythrocytes against complement-medi ated lysis by diluted normal human serum. There was a linear relationship b etween the concentration of clusterin giving 50% protection and the concent ration of serum; extrapolation of this to the case of undiluted human serum showed that a clusterin concentration at least two orders of magnitude gre ater than its physiological plasma concentration would be needed to confer protection against complement-mediated cytolysis under physiological condit ions. Physiological concentrations of clusterin did not protect rabbit eryt hrocytes against alternative complement pathway-mediated lysis using dilute human serum. Exogenous clusterin had no effect on lysis of human erythrocy tes triggered by the addition of inulin to autologous human serum. Inductio n of cell-surface clusterin expression by L929 (murine fibroblast) cells wh ich had been stably transfected with cDNA for human clusterin linked to DNA coding for the 44 C-terminal amino acid residues of CD55 did not protect t he cells against complement-mediated lysis by either normal or clusterin-de pleted human serum. These data suggest that clusterin may not be a physiolo gically relevant regulator of complement activation. (C) 1999 Academic Pres s.