Abstract
Hepatitis causes hepatic cell injury, regeneration and different levels of fibrogenesis, and severe liver fibrogenesis progresses into cirrhosis with liver dysfunction. Serum amyloid A (SAA) is an acute phase protein that is predominantly secreted by hepatocytes during early injury or infection. Nevertheless, the relationship of SAA and development of cirrhosis as well as the underlying molecular mechanisms is largely unknown. Here, we found that macrophages are the major SAA-binding cells in the injured liver. in vitro, macrophages treated with SAA exhibited high production of IL-10 but low production of IL-12, as features for M2 macrophages. Moreover, these polarized M2 macrophages by SAA also produced IL-1, IL-6 and TNFa, characteristics for an M2b subtype, rather than an alternative M2a or fibrogenic M2c subtype. In a mouse model of carbon tetrachloride (CCl(4))-induced hepatic fibrogenesis/cirrhosis, anti-SAA sera were used to block the effects of SAA, resulting in increases in the severity of hepatic fibrosis, suggesting an overall anti-fibrogenic effect of SAA. Isolated macrophages from mouse liver showed that anti-SAA appeared to alter the polarization of macrophages from M2b to M2c, suggesting that SAA may induce M2b-like macrophage polarization during liver inflammation, which prevents the liver from fibrogenesis.