Acute-phase proteins (APPs) are a class ofproteins whose concentrations inblood plasma either increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response toinflammation. This response is called theacute-phase reaction (also calledacute-phase response). The acute-phase reaction characteristically involvesfever, acceleration of peripheralleukocytes, circulatingneutrophils and their precursors.[1] The termsacute-phase protein andacute-phase reactant (APR) are often used synonymously, although some APRs are (strictly speaking)polypeptides rather than proteins.
In response toinjury, localinflammatorycells (neutrophil granulocytes andmacrophages) secrete a number ofcytokines into the bloodstream, most notable of which are theinterleukinsIL1, andIL6, andTNF-α. Theliver responds by producing many acute-phase reactants. At the same time, the production of a number of otherproteins is reduced; theseproteins are, therefore, referred to as "negative" acute-phase reactants. Increased acute-phase proteins from theliver may also contribute to the promotion ofsepsis.[2]
TNF-α,IL-1β andIFN-γ are important for the expression of inflammatory mediators such asprostaglandins andleukotrienes, and they also cause the production ofplatelet-activating factor andIL-6. After stimulation with proinflammatorycytokines,Kupffer cells produce IL-6 in the liver and present it to thehepatocytes. IL-6 is the major mediator for the hepatocytic secretion of APPs. Synthesis of APP can also be regulated indirectly bycortisol. Cortisol can enhance expression of IL-6receptors in liver cells and induce IL-6-mediated production of APPs.[1]
Positive acute-phase proteins serve (as part of the innate immune system) different physiological functions within theimmune system. Some act to destroy or inhibit growth ofmicrobes, e.g.,C-reactive protein,mannose-binding protein,[3]complement factors,ferritin,ceruloplasmin,serum amyloid A andhaptoglobin. Others givenegative feedback on the inflammatory response, e.g.serpins.Alpha 2-macroglobulin andcoagulation factors affectcoagulation, mainly stimulating it. This pro-coagulant effect may limitinfection by trappingpathogens in localblood clots.[1] Also, some products of the coagulation system can contribute to theinnate immune system by their ability to increase vascular permeability and act aschemotactic agents forphagocytic cells.[citation needed]
| Protein | Immune system function |
|---|---|
| C-reactive protein | Opsonin on microbes[4] (not an acute-phase reactant in mice) |
| Serum amyloid P component | Opsonin |
| Serum amyloid A |
|
| Complement factors | Opsonization,lysis and clumping of target cells.Chemotaxis |
| Mannan-binding lectin | Mannan-binding lectin pathway of complement activation |
| Fibrinogen,prothrombin,factor VIII, von Willebrand factor | Coagulation factors, trapping invading microbes in blood clots. Some cause chemotaxis |
| Plasminogen activator inhibitor-1 (PAI-1) | Prevents the degradation of blood clots by inhibitingtissue Plasminogen Activator (tPA) |
| Alpha 2-macroglobulin |
|
| Ferritin | Bindingiron, inhibiting microbe iron uptake[6] |
| Hepcidin[7] | Stimulates the internalization offerroportin, preventing release ofiron bound byferritin within intestinalenterocytes andmacrophages |
| Ceruloplasmin | Oxidizes iron, facilitating forferritin, inhibiting microbe iron uptake |
| Haptoglobin | Bindshemoglobin, inhibiting microbe iron uptake and prevents kidney damage |
| Orosomucoid (Alpha-1-acid glycoprotein, AGP) | Steroid carrier |
| Alpha 1-antitrypsin | Serpin, downregulates inflammation |
| Alpha 1-antichymotrypsin | Serpin, downregulates inflammation |
| Lipopolysaccharide binding protein (LBP) | Attaches to bacterialLPS, evoke immune responses viapattern recognition receptors[8] |
"Negative" acute-phase proteins decrease in inflammation. Examples includealbumin,[9]transferrin,[9]transthyretin,[9]retinol-binding protein,antithrombin,transcortin. The decrease of such proteins may be used as markers of inflammation. The physiological role of decreased synthesis of such proteins is generally to saveamino acids for producing "positive" acute-phase proteins more efficiently. Theoretically, a decrease in transferrin could additionally be decreased by an upregulation oftransferrin receptors, but the latter does not appear to change with inflammation.[10]
While the production of C3 (a complement factor) increases in the liver, the plasma concentration often lowers because of an increased turn-over, therefore it is often seen as a negative acute-phase protein.[citation needed]
Measurement of acute-phase proteins, especially C-reactive protein, is a useful marker of inflammation in both medical and veterinaryclinical pathology. It correlates with theerythrocyte sedimentation rate (ESR), however not always directly. This is due to the ESR being largely dependent on the elevation offibrinogen, an acute phase reactant with a half-life of approximately one week. This protein will therefore remain higher for longer despite the removal of the inflammatory stimuli. In contrast, C-reactive protein (with a half-life of 6–8 hours) rises rapidly and can quickly return to within the normal range if treatment is employed. For example, in activesystemic lupus erythematosus, one may find a raised ESR but normal C-reactive protein.[citation needed]They may also indicate liver failure.[11]
