Gene Expression Profile of Toll-Like Receptor Adaptor / Interferon Regulatory Factor Cytokine Axis During Liver Regeneration After Partial Ischemia-Reperfusion Injury

Objectives: Toll-like receptors and downstream signal transduction pathways play pivotal roles in induction of inflammation, which is crucial for liver injury and regeneration. Materials and Methods: Using a mouse model of partial hepatic ischemia-reperfusion injury followed by a 28-day time course for liver repair and regeneration, we assessed gene expression levels for Toll-like receptors, myeloid differentiation primary response 88, TIR-domain-containing adapter-inducing interferon-beta, nuclear factor kappa B, interferon regulatory factors, tumor necrosis factor-alpha, and interleukins 1 beta and 6 at days 1, 4, 7, 14, and 28 after reperfusion in liver and blood cells by quantitative polymerase chain reaction. Results: Mouse liver was gradually injured until 24 hours after reperfusion, and necrotic areas remained for 7 days. Concurrent with liver necrosis, overexpression of hepatocyte growth factor in blood cells (days 1-14), transient overexpression of cyclin D1 at day 7 in hepatic cells, and overexpression of transforming growth factor-beta 1 at days 7 and 14 in blood cells were used to characterize the priming, proliferative, and termination phases of liver regeneration. Liver regeneration was associated with significant up-regulation of Toll-like receptor 4, p65, interferon regulatory factors 1, 3, 9, tumor necrosis factor-alpha, and interleukin 1 beta at 24 hours. Liver regeneration was also associated with persistent overexpression of MyD88 (days 1-28) and with delayed TIR-domain-containing adapter-inducing interferon-beta (days 4-28) in hepatic cells. In peripheral blood cells, Toll-like receptor 2 and MyD88 were up-regulated at 24 hours and Toll-like receptor 4 (days 1-14) and interferon regulatory factor 1 (days 1-7) showed persistent overexpression concomitant with interferon regulatory factor 5 (days 7-14); interleukin 1 beta (days 1-28) and interleukin 6 (day 4-28) also showed persistent expression. Conclusions: We depict for the first time a prospective view of cooperative transcriptional activation of Toll-like receptors/adaptors/interferon regulatory factors/cytokines in both liver and blood cells during different phases of liver repair after ischemia-reperfusion injury.