Tightly regulated induction of the adhesion molecule necl-5/CD155 during rat liver regeneration and acute liver injury

Abstract

TuAg1/TagE4, the rat ortholog of the human poliovirus receptor CD155, is expressed on a high percentage of rat hepatocellular carcinomas. Recent studies have shown that TuAg1/TagE4/CD155 is a member of the nectin family of immunoglobulin (Ig)-like cell adhesion molecules, designated necl-5. Necl-5 is present at exceedingly low levels in adult epithelial tissues but is upregulated in primary cultures of rat hepatocytes, suggesting that disruption of liver architecture triggers its expression. To explore this possibility, we examined expression of necl-5 after two-thirds partial hepatectomy or carbon tetrachloride (CCl4)-induced acute injury. Using quantitative real-time polymerase chain reaction (QPCR), we found that necl-5 mRNA levels increased 15-fold by 9 hours, and decreased to 4-fold above baseline by 24 hours after partial hepatectomy. Necl-5 mRNA levels increased over 100-fold 6 hours after treatment with CCl4, reaching a peak of 140-fold above baseline by 10 hours, and thereafter rapidly declining. Necl-5 was localized at the membrane of midlobular and centrilobular hepatocytes 10 to 48 hours after CCl4 exposure. Northern blot analysis demonstrated a close correlation between the kinetics of necl-5 expression and the immediate-early response gene c-myc. Subconfluent cultures of the non-transformed liver epithelial cell line WB-F344 expressed high levels of necl-5, which was down-regulated as cells approached confluence. The transformed WB-F344 line GP7TB did not demonstrate density-dependent regulation of necl-5 expression. In conclusion, we report the in vivo induction of necl-5 in rat hepatocytes and provide evidence that both necl-5 mRNA and protein are tightly regulated in adult epithelial cells and tissue.