Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase or decrease in response to inflammation.
An increase in the concentration of serum proteins that are referred to as acute phase reactants (APR) accompanies inflammation.
This response is called the acute-phase reaction.
During the acute phase response, the usual levels of plasma proteins ordinarily maintained by homeostatic mechanisms can change significantly.
These changes are thought to contribute to host defense and other adaptive capabilities.
The acute phase response accompanies chronic as well as acute inflammatory states and is associated with a wide variety of disorders, including infection, trauma, infarction, inflammatory arthritides, other systemic autoimmune and inflammatory diseases, and various neoplasms.
Less marked changes may occur in response to metabolic stresses.
The acute-phase reaction characteristically involves fever, acceleration of peripheral leukocytes, circulating neutrophils and their precursors.
In response to injury, local inflammatory cells, neutrophil granulocytes and macrophages, secrete a number of cytokines into the bloodstream, most notable of which are the interleukins IL1, and IL6, and TNF-α.
The liver responds to inflammation by producing many acute-phase reactants.
Simultaneously the production of a number of other proteins is reduced; these proteins are, therefore, referred to as “negative” acute-phase reactants.
Increased acute-phase proteins from the liver may also contribute to the promotion of sepsis.
TNF-α, IL-1β and IFN-γ are important for the expression of inflammatory mediators such as prostaglandins and leukotrienes, and they also cause the production of platelet-activating factor and IL-6.
The Kupffer cells produce IL-6 in the liver and present it to the hepatocytes after stimulation with proinflammatory cytokines.
IL-6 is the major mediator for the hepatocytic secretion of acute-phase proteins.
Synthesis of acute-phase proteins can also be regulated indirectly by cortisol.
Cortisol can enhance expression of IL-6 receptors in liver cells and induce IL-6-mediated production of acute-phase proteins.
Positive acute-phase proteins serve are part of the innate immune system and serve different physiological functions within the immune system.
Positive acute-phase proteins act to destroy or inhibit growth of microbes C-reactive protein, mannose-binding protein,
complement factors, ferritin, ceruloplasmin, serum amyloid A and haptoglobin.
Other acute-phase proteins give negative feedback on the inflammatory response, e.g. serpins.
Alpha 2-macroglobulin and coagulation factors affect coagulation, mainly stimulating it.
This pro-coagulant effect may limit infection by trapping pathogens in local blood clots.
Some products of the coagulation system contribute to the innate immune system by their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells.
Acute phase proteins are defined as those proteins whose serum concentrations increase or decrease by at least 25 percent during inflammatory states.
Such proteins are termed either positive or negative acute phase reactants,respectively.
The erythrocyte sedimentation rate (ESR), an indirect acute phase reactant that reflects plasma viscosity and the presence of acute phase proteins, especially fibrinogen, as well as other influences.
An increase in the concentration of acute phase reactants (APR) accompanies inflammation.
Changes in the levels of APR largely reflect altered production by hepatocytes.
Such change result primarily from the effects of cytokines produced during the inflammatory process by macrophages, monocytes, and a variety of other cells.
These cytokines also suppress the synthesis of albumin, termed a negative acute phase reactant because its levels decrease with inflammation.
Combinations of cytokines can have additive, inhibitory, or synergistic effects,
Patterns of cytokine production differ under various inflammatory conditions.
Increases in APR can vary from approximately 50 percent for ceruloplasmin and several components of the complement cascade to 1000-fold or more for C-reactive protein (CRP) and serum amyloid A (SAA).
Positive APR include: fibrinogen, levels of which have substantial effects on the ESR; alpha-1 antitrypsin; haptoglobin; IL-1 receptor antagonist; hepcidin; ferritin; procalcitonin; and others.
Negative APR include albumin, transferrin, and transthyretin.
Changes in the levels of acute phase proteins is largely a reflection of altered production by hepatocytes, due to the effects of cytokines produced during an inflammatory process by macrophages, monocytes, and other cells.
Interleukin (IL) 6 is the major inducer of most acute phase proteins.
Some of the other major cytokines relevant to the acute phase response are IL-1 beta, tumor necrosis factor (TNF)-alpha, and interferon gamma.
These cytokines also suppress the synthesis of albumin, termed a negative APR because its levels decrease with inflammation
Combinations of cytokines have additive, inhibitory, or synergistic effects.
Patterns of cytokine production differ under various inflammatory conditions.
APR increases can vary from approximately 50 percent for ceruloplasmin and several components of the complement cascade to 1000-fold or more for C-reactive protein (CRP) and serum amyloid A (SAA).
Additional positive APR include fibrinogen, levels of which have substantial effects on the ESR; alpha-1 antitrypsin; haptoglobin; IL-1 receptor antagonist; hepcidin; ferritin; and procalcitonin.
Negative APR include: albumin, transferrin, and transthyretin.
Positive acute-phase proteins:
C-reactive protein
Opsonin
Serum amyloid P component
Serum amyloid A
Recruitment of immune cells to inflammatory sites
Induction of enzymes that degrade extracellular matrix
Complement factors
Opsonization, lysis and clumping of target cells.
Chemotaxis
Mannan-binding lectin
Fibrinogen,
prothrombin,
factor VIII,
von Willebrand factor
Coagulation factors, trapping invading microbes in blood clots.
Plasminogen activator inhibitor-1 (PAI-1)-Prevents the degradation of blood clots by inhibiting tissue Plasminogen Activator (tPA)
Alpha 2-macroglobulin
Inhibitor of coagulation by inhibiting thrombin.
Inhibitor of fibrinolysis by inhibiting plasmin
Ferritin-Binding iron, inhibiting microbe iron uptake.
Hepcidin-Stimulates the internalization of ferroportin, preventing release of iron bound by ferritin within intestinal enterocytes and macrophages
Ceruloplasmin-Oxidizes iron, facilitating for ferritin, inhibiting microbe iron uptake
Haptoglobin Binds hemoglobin, 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
Negative acute-phase proteins decrease with inflammation:
albumin, transferrin, transthyretin,retinol-binding protein, antithrombin, and transcortin.
Decreases of such proteins may be used as markers of inflammation.
The production of C3 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.
Measurement of acute-phase proteins, especially C-reactive protein, is a useful marker of inflammation.
It correlates with the erythrocyte sedimentation rate (ESR), however not always directly.
The ESR being largely dependent on the elevation of fibrinogen, an acute phase reactant with a half-life of approximately one week:
It remains 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.