RANTES can also directly target HSCs to promote their proliferation and migration, and mice deficient for RANTES or its receptors chemokine (C-C) motif GSK-3 beta pathway receptor 1 (CCR1) and CCR5 display substantially reduced fibrosis.30 Here, we show that deficiency of c-Rel is associated with substantially reduced baseline and injury-induced expression of RANTES, which may therefore help explain the reduced numbers of recruited neutrophils, lower numbers of α-SMA+ HSCs, and the attenuated

fibrogenic response. However, using the culture model of HSC transdifferentiation, we also discovered inherent defects in c-rel−/− HSCs, specifically reduced expression of collagen I and α-SMA transcripts. NF-κB is a regulator of HSC survival and their expression of inflammatory regulators intercellular cell adhesion molecule-1 and interleukin-6.31 Pharmacological blockade of NF-κB can promote HSC apoptosis and regression of liver fibrosis.32, 33 However, the precise contribution of the individual NF-κB subunits toward the fate and function of HSCs has not been investigated. Our previous report that the p50 subunit is a suppressor of the inflammatory properties of HSC-derived myofibroblasts,13 taken together with the potential for c-Rel

to regulate expression of collagen I, α-SMA, and RANTES suggests the need for detailed studies of the functions of the NF-κB subunits in HSCs and fibrosis. Nonparenchymal cells, including HSCs, can influence liver regeneration through paracrine stimulation of hepatocyte proliferation.34 Defective function of the inflammatory and BMS-777607 supplier fibrogenic compartments may therefore contribute to the attenuated DNA synthesis and mitosis of hepatocytes observed Acetophenone in injured and PHx livers of c-rel−/− mice. However, we propose that c-Rel also plays a more direct role as a regulator of hepatocyte DNA replication. B cells deficient in c-Rel display deficiencies in cyclin

D3 and cyclin E expression, cyclin-dependent kinase activity, Rb phosphorylation, and E2F activity and fail to progress through the cell cycle in response to B cell receptor stimulation.35 Because ChIP analysis confirmed recruitment of c-Rel to the FoxM1 promoter following PHx, we suggest that c-Rel regulates hepatocyte proliferation via transcriptional control of the cell cycle regulator FoxM1, which following PHx, was not induced at the appropriate time or level of expression in c-Rel–deficient livers. FoxM1 regulates proliferation of many cell types and in the developing liver and heart is essential for normal mitosis.36 Expression profiling identified a cluster of FoxM1-regulated genes including G2/M-specific genes such as cyclin B1 and CENP-F (centromere protein F).37 In particular, transcriptional activation of cyclin B1 by FoxM1 is crucial for timely mitosis.37 Induction of cyclin B1 was delayed in the regenerating c-Rel–deficient liver.