An acute phase protein ready to go therapeutic for sepsis

The so-called Acute Phase Response (APR) begins between 12 and 48 h after the initiation of inflammation. This conserved response mainly involves the production of a set of Acute Phase Proteins (APPs) and the downregulation of other proteins (negative APPs) by hepatocytes. Although the precise identity of the APPs may differ between species, some APPs are common in all mammals. The APR is regulated by two major players, glucocorticoids and Interleukin-6 (IL-6). Indeed, most APP coding genes contain glucocorticoid receptor responsive (GRE) elements as well as nuclear factor for IL-6 expression (NF-IL6) responsive elements (Cray et al, 2009). Also, other family members of IL-6, for example IL-11, can induce the APR. APPs are curious in several ways. First, their production is remarkably slow. Second, they are very diverse, and except for a few, their biological activities are poorly understood. And third, the function of the APR remains unclear. Conserved APPs include C-reactive protein (CRP), alpha-1-acid glycoprotein, alpha-1-antitrypsin, serum amyloid A, serum amyloid P, and alpha-2-macroglobulin (A2MG). Some of these proteins are hardly detectable in healthy mammals but are induced 10–1000-fold during inflammation. Because many of these APPs are heavily glycosylated (by liver enzymes that also behave like APPs), they are very stable. That is why some APPs are ideal biomarkers of inflammation, of which CRP is a typical and wellknown example (Pepys & Hirschfield, 2003). The slow production of APPs and the known biological activities of some of them indicate that they form a negative feedback loop involved in containing pathogens and limiting the inflammatory cascade. For example, alpha-1-acid glycoprotein has strong anti-inflammatory activities only at high concentrations (thus with poor specificity), and its mechanism of action is unknown but could be based on inhibition of white blood cell over-activation (Libert et al, 1994). Other APPs have more defined biological activities but they have to be given in high concentrations to have anti-inflammatory effects. Alpha-1-antitrypsin, the major neutrophil elastase inhibitor is one of them (Libert et al, 1996). ...................................................... “... some APPs are ideal biomarkers of inflammation” ......................................................