Although it is well established that hepatic macrophages play a crucial role in the development of liver fibrosis, the underlying mechanisms remain largely elusive. Moreover, it is not known whether other mononuclear phagocytes such as dendritic cells contribute to hepatic stellate cell (HSC) activation and liver fibrosis. Here we show for the first time that hepatic macrophages enhance myofibroblast survival in an NF-κB-dependent manner, and thereby promote liver fibrosis. Microarray and pathway analysis revealed no induction of HSC activation pathways by hepatic macrophages but a profound activation of the nuclear factor-kappa B (NF-κB) pathway in HSCs. Conversely, depletion of mononuclear phagocytes during fibrogenesis in vivo resulted in suppressed NF-κB activation in HSCs. Macrophage-induced activation of NF-κB in HSC in vitro and in vivo was mediated by IL-1 and TNF. Notably, IL-1 and TNF did not promote HSC activation but promoted survival of activated HSC in vitro and in vivo and thereby increased liver fibrosis, as demonstrated by neutralization in co-culture experiments, and genetic ablation of IL-1 and TNF receptor in vivo. Co-culture and in vivo ablation experiments revealed only a minor contribution to NF-κB activation in HSCs by dendritic cells, and no contribution of dendritic cells to liver fibrosis development, respectively. Conclusion Promotion of NF-κB-dependent myofibroblast survival by macrophages but not dendritic cells provides a novel link between inflammation and fibrosis.

In patients who underwent curative treatment for HCC, adjuvant immunotherapy with activated CIK cells increased recurrence-free and overall survival. ClinicalTrials.gov number: NCT00699816.

Hepatic fibrosis develops as a response to chronic liver injury and almost exclusively occurs in a proinflammatory environment. However, the role of inflammatory mediators in fibrogenic responses of the liver is only poorly understood. We therefore investigated the role of CC chemokines and their receptors in hepatic fibrogenesis. The CC chemokines MIP-1α, MIP-1β, and RANTES and their receptors CCR1 and CCR5 were strongly upregulated in 2 experimental mouse models of fibrogenesis. Neutralization of CC chemokines by the broadspectrum CC chemokine inhibitor 35k efficiently reduced hepatic fibrosis, and CCR1-and CCR5-deficient mice displayed substantially reduced hepatic fibrosis and macrophage infiltration. Analysis of fibrogenesis in CCR1-and CCR5-chimeric mice revealed that CCR1 mediates its profibrogenic effects in BM-derived cells, whereas CCR5 mediates its profibrogenic effects in resident liver cells. CCR5 promoted hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent pathway. Both CCR5-deficient HSCs and CCR1-and CCR5-deficient Kupffer cells displayed strong suppression of CC chemokine-induced migration. Finally, we detected marked upregulation of RANTES, CCR1, and CCR5 in patients with hepatic cirrhosis, confirming activation of the CC chemokine system in human fibrogenesis. Our data therefore support a role for the CC chemokine system in hepatic fibrogenesis and suggest distinct roles for CCR1 and CCR5 in Kupffer cells and HSCs.

The use of potent oral antiviral therapy can effectively suppress HBV replication in patients with CHB. However, the risk of HCC development in patients treated with oral antiviral agent is still significantly higher than patients with inactive stage CHB.