Acute-phase protein

Acute-phase proteins (APPs) are a class

of proteins whose plasma concentrations
increase (positive acute-phase proteins) or
decrease (negative acute-phase proteins)
in response to inflammation. This
response is called the acute-phase reaction
(also called acute-phase response). For
acute-phase reaction is characteristic
fever, acceleration of peripherals
leukocytes, circulating neutrophils and
their precursors.[1] The terms acute-phase
protein and acute-phase reactant (APR) are
often used synonymously, although some
APRs are (strictly speaking) polypeptides
rather than proteins.

Inflammatory cells and red blood cells

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 TNFα. The liver responds by
producing a large number of acute-phase
reactants. At the same time, 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.[2]

Regulation of synthesis
TNF-α, IL-1β and INF-γ are important for
the expression of inflammatory mediators
as prostagladins and leukotrienes and
they also cause the production of platelet-
activating factor and IL-6. After stimulation
of proinflammatory cytokines, Kupffer
cells produce IL-6 in the liver and present it
to the hepatocytes. IL-6 is the major
mediator for the hepatocytic secretion of
APPs. Synthesis of APP can be also
regulated indirectly by cortisol. Cortisol
can enhance expression of IL-6 receptors
in liver cells and induce IL-6-mediated
production of APPs.[1]  

Positive
Positive acute-phase proteins serve (as
part of the innate immune system)
different physiological functions within the
immune system. Some act to destroy or
inhibit growth of microbes, e.g., C-reactive
protein, mannose-binding protein,[3]
complement factors, ferritin,
ceruloplasmin, serum amyloid A and
haptoglobin. Others 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.[1] Also,
some products of the coagulation system
can contribute to the innate immune
system by their ability to increase vascular
permeability and act as chemotactic
agents for phagocytic cells.
"Positive" acute-phase proteins:
Protein Immune system function

C-reactive protein Opsonin on microbes[4] (not an acute-phase reactant in mice)

Serum amyloid P
Opsonin
component

Recruitment of immune cells to inflammatory sites

Serum amyloid A
Induction of enzymes that degrade extracellular matrix

Complement factors Opsonization, lysis and clumping of target cells. Chemotaxis

Mannan-binding
Mannan-binding lectin pathway of complement activation
lectin

Fibrinogen,
prothrombin, factor Coagulation factors, trapping invading microbes in blood clots.
VIII, Some cause chemotaxis
von Willebrand factor

Plasminogen
Prevents the degradation of blood clots by inhibiting tissue
activator inhibitor-1
Plasminogen Activator (tPA) [5]
(PAI-1)

Alpha 2- Inhibitor of coagulation by inhibiting thrombin.[6]

macroglobulin Inhibitor of fibrinolysis by inhibiting plasmin

Ferritin Binding iron, inhibiting microbe iron uptake [7]

Stimulates the internalization of ferroportin, preventing release of iron

Hepcidin[8]
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 Steroid carrier
glycoprotein, AGP)

Alpha 1-antitrypsin Serpin, downregulates inflammation

Alpha 1-
Serpin, downregulates inflammation
antichymotrypsin
Negative
"Negative" acute-phase proteins decrease
in inflammation. Examples include
albumin,[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
save amino acids for producing "positive"
acute-phase proteins more efficiently.
Theoretically, a decrease in transferrin
could additionally be decreased by an
upregulation of transferrin receptors, but
the latter does not appear to change with
inflammation.[10]

Clinical significance
Measurement of acute-phase proteins,
especially C-reactive protein, is a useful
marker of inflammation in both medical
and veterinary clinical pathology. It
correlates with the erythrocyte
sedimentation rate (ESR), however not
always directly. This is due to the ESR
being largely dependent on elevation of
fibrinogen, an acute phase reactant with a
half-life of approximately one week. This
protein will therefore remain higher for
longer despite 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 active systemic
lupus erythematosus, one may find a
raised ESR but normal C-reactive protein.

They may also indicate liver failure.[11]

See also
Wikipedia:MeSH D12.776#MeSH
D12.776.124.050 --- acute-phase
proteins
References
1. Jain S, Gautam V, Naseem S (January
2011). "Acute-phase proteins: As
diagnostic tool" . Journal of Pharmacy
& Bioallied Sciences. 3 (1): 118–27.
doi:10.4103/0975-7406.76489 .
PMC 3053509 . PMID 21430962 .
2. Abbas A, Lichtman A, Pillai S (2012).
Basic immunology Functions and
Disorders of the Immune System (4th
ed.). Philadelphia, PA:
Saunders/Elsevier. p. 40.
3. B L Herpers, H Endeman, B A W de
Jong, B M de Jongh, J C Grutters, D H
Biesma, and H van Velzen-Blad. Acute-
 phase responsiveness of mannose-
binding lectin in community-acquired
pneumonia is highly dependent upon
MBL2 genotypes. Clin Exp Immunol.
2009 Jun;156(3):488-94.
PMID 19438602
4. Lippincott's Illustrated Reviews:
Immunology. Paperback: 384 pages.
Publisher: Lippincott Williams &
Wilkins; (July 1, 2007). Language:
English. ISBN 0-7817-9543-5.
ISBN 978-0-7817-9543-2. Page 182
5. Davidson SJ (24 July 2013).
"Inflammation and Acute Phase
Proteins in Haemostasis". In
 Janciauskiene S (ed.). Acute Phase
Proteins. doi:10.5772/55998 .
6. de Boer JP, Creasey AA, Chang A,
Abbink JJ, Roem D, Eerenberg AJ, et
al. (December 1993). "Alpha-2-
macroglobulin functions as an
inhibitor of fibrinolytic, clotting, and
neutrophilic proteinases in sepsis:
studies using a baboon model".
Infection and Immunity. 61 (12):
5035–43. PMID 7693593 .
7. Koorts AA, Viljoen M (2011). "Acute
Phase Proteins: Ferritin and Ferritin
Isoforms" (PDF). In Veas F (ed.).
 Acute Phase Proteins. InTech.
doi:10.5772/20586 .
8. Vecchi C, Montosi G, Zhang K, et al.
(August 2009). "ER stress controls iron
metabolism through induction of
hepcidin" . Science. 325 (5942): 877–
80. doi:10.1126/science.1176639 .
PMC 2923557 . PMID 19679815 .
9. Ritchie RF, Palomaki GE, Neveux LM,
Navolotskaia O, Ledue TB, Craig WY
(1999). "Reference distributions for the
negative acute-phase serum proteins,
albumin, transferrin, and transthyretin:
a practical, simple and clinically
relevant approach in a large cohort". J.
 Clin. Lab. Anal. 13 (6): 273–9.
doi:10.1002/(SICI)1098-
2825(1999)13:6<273::AID-
JCLA4>3.0.CO;2-X . PMID 10633294 .
10. Chua E, Clague JE, Sharma AK, Horan
MA, Lombard M (October 1999).
"Serum transferrin receptor assay in
iron deficiency anaemia and anaemia
of chronic disease in the elderly" .
QJM. 92 (10): 587–94.
doi:10.1093/qjmed/92.10.587 .
PMID 10627880 .
11. Ananian P, Hardwigsen J, Bernard D, Le
Treut YP (2005). "Serum acute-phase
protein level as indicator for liver
 failure after liver resection".
Hepatogastroenterology. 52 (63):
857–61. PMID 15966220 .

External links
Acute-Phase+Proteins at the US
National Library of Medicine Medical
Subject Headings (MeSH)

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