Interleukin 18 accelerates the hepatic cell proliferation in rat liver regeneration after partial hepatectomy

Abstract

Interleukin 18 (IL-18) is a proinflammatory cytokine with an ability to accelerate cell proliferation through activating other factors. However, little is yet understood of the role of IL-18 in the regulation of liver regeneration (LR). To study the effect of IL-18 on LR, the gene expression profiles of hepatocytes isolated from rat regenerative liver were determined by Rat Genome 230 2.0 microarray. Next, the synergistic effects of genes associated to IL-18 pathway were analyzed by expression profile function Et. Then, the expression level of IL-18 was examined by RT-PCR and ELISA. Finally, the effect of IL-18 on hepatocyte proliferation was detected by injecting recombinant rat IL-18 (rrIL-18) into rats immediately after partial hepatectomy (PH) and the rate of hepatocyte proliferation was detected by BrdU labeling. The microarray result showed that the expressions of 13 genes of IL-18 pathway and 49 cell proliferation genes regulated by the pathway were significantly altered at transcriptional level. The Et values of three branches of IL-18 pathway, NF-κB, p38 and JNK, were markedly enhanced during the priming and progressing phases of rat LR. The mRNA level of IL-18 was significantly elevated at 2 and 36 h, and its level in plasma was also significantly increased at 2h, and reached the peaks at 12h and 48 h after PH (p<0.05). The number of BrdU positive cells was dramatically increased in rats treated with IL-18 compared to PBS control group (p<0.01). In conclusion, IL-18 promotes rat hepatocyte proliferation in the LR priming and progressing phases after PH.

Keywords: 4′6′-diamidino-2-phenylindole dihydrochloride; BrdU; DAPI; EDTA; ELISA; Gene expression profile; Hepatocyte proliferation; IGIF; IL-18; IL-18R; IPA; Ingenuity Pathway Analysis; Interleukin-18; LR; Liver regeneration; PH; RT-PCR; SO; bromodeoxyuridine; enzyme-linked immuno-sorbent assay; ethylene diamine tetraacetic acid; interferon-γ-inducing factor; interleukin 18; interleukin 18 receptor; liver regeneration; partial hepatectomy; real-time polymerase chain reaction; recombinant rat interleukin 18; rrIL-18; sham operation.