The Role of the Acute-Phase Proteins in the Development and Progression of Liver Diseases

Abstract

The liver is a unique organ that is rich in cellular effectors for diverse systems, including the innate immune system, which plays a central role in hepatocellular injury (Gabay & Kushner, 1999). The innate immune system is based on broadly specific antigen recognition and does not rely on the more specialized antigen recognition pathways of the adaptive immune system. Although the innate immune response has broad specificity and is complex, acute-phase proteins (APPs) have been identified as biomarkers of the innate response (Table 1). APPs are mostly synthesized in the liver. Their concentrations in plasma increase (positive APPs) or decrease (negative APPs) by at least 25% during inflammatory disorders. Most changes in APP concentration are due to infection, trauma, surgery, burns, tissue infarction, immunologically mediated or crystal-induced inflammation, and advanced cancer. Exercise, heatstroke, childbirth, or even psychological stress and some psychiatric disorders may also affect concentrations of these proteins. Cytokines are the chief stimulators and regulators of the production of these proteins. Interleukin (IL)-6 is the principal stimulator of APPs but other proinflammatory cytokines such as IL-1, tumor necrosis factor alpha (TNF-), interferon gamma (INF-), and transforming growth factor beta (TGF-), and chemokines such as IL-8 are also involved. In the liver, the Janus kinase signal transducer and activator of transcription (STAT) pathway has been implicated in the action of cytokines. STAT 1 and STAT 2, which are activated by INF-/, are involved in antiviral defense and the former is involved in liver inflammation and injury. STAT 3 has been implicated in the acute-phase response as well as in hepatoprotective effects and liver regeneration. This pathway is mostly activated by IL-6. STAT 4 and STAT 6 are associated with the ischemia/reperfusion cycle as promoters of and protectors against injury, respectively, and STAT 5 plays an important role in the regulation of hepatic genes and growth factors. Several studies have confirmed that IL-6 and IL-22 (a related cytokine) are responsible for important liver functions such as liver regeneration, glucose and lipid metabolism, and induction of antiapoptotic proteins (Gao, 2005).