Mechanism of direct hepatotoxic effect of KC chemokine: sequential activation of gene expression and progression from inflammation to necrosis.

This work aimed to show that an important, yet unrecognized, role of KC chemokine in the liver is regulation of gene expression. KC expression in the liver stimulated three classes of genes in this temporal order: immediate-early genes, proinflammatory genes, and profibrotic genes. Transcription factors E2F5 and early growth response 1 (EGR1), Ca(2+) signaling molecules S100A8 and S100A9, and two oxidative stress-induced genes were identified as immediate-early genes of KC. Expression of these genes was stimulated at 3-5-fold increased KC concentrations. Expression of proinflammatory genes was activated 6 h after the immediateearly genes, and they included interleukin-1alpha (IL-1alpha) and IL-1beta. KC receptor gene CXCR2 was also upregulated, suggesting that KC may act through a positive feedback loop. Stimulation of expression of profibrotic genes, including type I collagen, was seen only after the proinflammatory genes were highly expressed for 12 h. KC is a potent regulator of gene expression that proceeds in a sequential manner. Immediate-early genes of KC stimulation were identified. The positive feedback regulation and an increased oxidative stress induced by KC may explain the poor prognosis in liver patients with elevated levels of CXC chemokines.