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Ramadori. Hepatoma Res 2020;6:28 I http://dx.doi.org/10.20517/2394-5079.2020.43 Page 5 of 10

Figure 3. Autoradiograph of a SDS-PAGE-analysis of radioactively labelled albumin from the supernatants of hepatocytes treated with the
first recombinant IL-1 for different time lengths (panel A). Panel B demonstrates that the inhibitory effect of IL-1 on albumin synthesis is
reversible (kinetic of release of the effect of the cytokine). J Exp Med 185;168:930-42. (reprinted with permission) [49]

of the large and small bowel [47,48] . The liver, as the source of the majority of the serum proteins, is the main
target of the acute phase cytokines. These cytokines induce pretranslational modification of gene expression
[49]
through direct interaction with the hepatocytes [Figure 3]. There are positive and negative acute phase
[45]
proteins .
According to the variations of their serum level, the positive acute-phase proteins are defined “major”, not
because of the volume of their serum level, but because of the magnitude (up to 1.000 fold) of the increase in
their serum level.

[51]
[50]
[56]
CRP, Serum Amyloid A, Serum Amyloid P, lactoferrin , Lipocalin-2 , hepcidin [52-55] , Interleukin-8 ,
[57]
and Erythropoietin all belong to the “major” acute-phase secretory protein group, while hemoxygenase-1
[58]
belongs to the positive intracellular acute-phase proteins. “Minor” acute-phase proteins are fibrinogen,
fibronectin, ceruloplasmin, alpha-1-antitrypsin, complement fraction 3, Factor B, and many others.
As most of the major acute-phase proteins have a low molecular weight, measurement of their serum level
may not correspond to a real increase in hepatic synthesis. This is due to the rapid elimination via the urine.
[59]
Hepcidin was first identified in the urine .
[49]
Albumin is the main negative secretory acute phase protein [Figure 4] , whilst ferroportin-1 and
hemojuvelin belong to the negative intracellular acute-phase protein group [52-55] . In a rat model, albumin
mRNA in the liver was reduced by 50%, while total mRNA was increased by 50%, 2 days after infection with
[60]
live Escherichia Coli . During the 2 days rats ate only 5%-10% of the amount of food consumed prior to
[60]
injection by the bacteria. This was followed by a further aggravation of the reduction of albumin synthesis ,
[62]
[61]
further demonstrated in isolated liver perfusion studies , and in humans under caloric restriction . The
amount of the acute-phase cytokines released into the circulation, and the concentration needed for the
systemic appearance of the symptoms and of the metabolic changes, are different in different patients. They
may be regulated differently by the drug administered, especially in the acute diseases. However, the response
is mainly proportional to the extent of the tissue damage.