Functional modification of CD11c+ liver dendritic cells during liver regeneration after partial hepatectomy in mice

Abstract

Local immunosuppression within the liver and sex steroid changes, in both blood and tissue during liver regeneration, are well-recognized events. Dendritic cells (DC) play pivotal roles in the induction and regulation of immune responses. Their numbers are expanded markedly in vivo by fms-like tyrosine kinase 3 ligand (Flt3L) administration, without modification of their maturation state. Recent evidence suggests that estrogen can modulate DC function and promote a Th2-type immune response. Few data are available concerning the role of DC in liver regeneration. After 75% partial hepatectomy (PH) in male C57BL/6 mice, CD11c⁺ liver (L)DC increased significantly within 6 hours and maintained an immature phenotype. Numbers returned to pre-hepatectomy levels by 24 hours. The expanded LDC population showed increased IL-10 and reduced IFN-γ gene transcription. Using these DC compared with control LDC as T cell stimulators in 72-hour mixed leukocyte cultures, IL-10 production was enhanced and IFN-γ production reduced. LDC isolated 6 hours after 75% PH exhibited enhanced estrogen receptor (ER) expression, concomitant with increased serum estrogen levels. By contrast, spleen (S)DC isolated before and after PH showed no significant changes in their function (maturation state, T cell stimulatory activity, cytokine production, and ER expression). Increased liver regeneration (more than 50%) was observed 48 hours after 40% PH in the Flt3L-pretreated compared with the PBS group. In conclusion, interstitial LDC may play a key role in local immune regulation during liver regeneration, possibly linking estrogen-mediated immune modulation and hepatocyte proliferation. (HEPATOLOGY 2006;43:807–816.)