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Acutephase Proteins

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 Acute Phase Proteins
David Samols1, Alok Agrawal1 and Irving Kushner2,*
1
Department of Biochemistry, Case Western Reserve University, School of Medicine, 10900 Euclid
Avenue, Cleveland, OH 44106-4935, USA
2
Department of Medicine, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth
Drive, Cleveland, OH 44109, USA
* corresponding author tel: (216) 778-4765, fax: (216) 778-8376, e-mail: ikushner@metrohealth.org
DOI: 10.1006/rwcy.2002.0213.
INTRODUCTION
The concentrations of many plasma proteins increase
during inflammatory states, largely in response to
inflammation-associated cytokines. C-reactive pro-
tein (CRP), the first such protein to be recognized,
was initially detected in serum obtained from patients
during the acute phase of pneumococcal pneumonia,
hence the term `acute phase proteins' (APP). APPs
are commonly defined as plasma proteins whose
concentrations increase (positive acute phase pro-
teins) by at least 25% during inflammatory states. In
addition, a number of negative acute phase proteins,
whose concentrations decrease significantly under
these circumstances, have been recognized. All of
these changes largely reflect altered production by
hepatocytes. Maximal increases vary from about 50%
in the case of ceruloplasmin and several complement
components to over 1000-fold for CRP and serum
amyloid A (SAA), the plasma precursor of amyloid A
(the major constituent of secondary amyloid depos-
its). The best-studied human acute phase proteins are
tabulated in Table 1.
APPs are generally comparable in different
mammalian species, with several noteworthy excep-
tions. For example, CRP, normally a trace protein in
humans, rabbits, and mice, is massively induced
(increases of a 1000-fold or more) by potent
inflammatory stimuli in humans and rabbits, but is
only minimally induced in mice. In contrast, CRP is
constitutively expressed at relatively high levels in
rats, with only a several-fold increase following
stimulus. Other examples are 2-macroglobulin
(2M), a major acute phase protein in the rat but
Cytokine Reference
not in humans, haptoglobin, a modest acute phase
reactant in humans, but a major acute phase reactant
in ruminants (in which it is normally undetectable)
(Sheffield et al., 1994), and serum amyloid P, an acute
phase reactant in mice but not in humans (Pepys et al.,
1979).
There are occasional interspecies problems in
terminology, exemplified by the revision of SAA
nomenclature in 1999 (Sipe, 1999). SAA is a family of
genes consisting of three genes and a pseudogene in
humans and four genes in mice. SAA1 and SAA2 are
major acute phase genes in humans, while SAA4 is
only modestly induced in inflammation and SAA3 is
a pseudogene. In mice, Saa1, Saa2, and Saa3 are
acute phase genes while Saa4 is a modest acute phase
reactant and a pseudogene is designated SAA-psl.
Acute phase plasma protein changes occur in the
context of a very large number of other changes,
distant from inflammatory sites and occurring in
many organ systems, that are detectable within
hours after the onset of an inflammatory response
(Table 2) (Gabay and Kushner, 1999; Kushner, 1982),
and can be regarded as the acute phase response
(APR) in a broad sense. An APR comparable to that
in humans is seen in all vertebrates, while lower
species manifest lesser responses. At times there is an
interrelationship between elements of the broad,
systemic APR and individual APP. For example, a
large number of changes in lipid metabolism occur
during inflammatory states (Khovidhunkit et al.,
2000), one of which is substantial replacement of
the ApoA1 ordinarily found in association with the
HDL3 fraction of lipoproteins by SAA (Coetzee et al.,
1986).
Copyright # 2002 Published by Elsevier Science Ltd
2 David Samols, Alok Agrawal and Irving Kushner

Table 1 Some human acute phase proteins

Proteins whose plasma Proteins whose plasma

concentrations increase concentrations decrease

Complement system Albumin

C3 Transferrin
C4 Transthyretin
C9 2 HS glycoprotein
Factor B -Fetoprotein
C-1 inhibitor Thyroxine-binding globulin
C4b-binding protein Factor XII
Mannan-binding lectin Retinol-binding protein
Participants in inflammatory responses Protein C
Lipopolysaccharide-binding protein
Granulocyte colony-stimulating factor
IL-1 receptor antagonist
Secretory phospholipase A2
Coagulation and fibrinolytic systems
Fibrinogen
Plasminogen
Tissue plasminogen activator
Plasminogen activator inhibitor-
Urokinase
Protein-S
Vitronectin
Antiproteases
1-Protease inhibitor
1-Antichymotrypsin
Pancreatic secretory trypsin inhibitor
Inter--trypsin inhibitors
Transport proteins
Ceruloplasmin
Haptoglobin
Hemopexin
Others
C-reactive protein
Serum amyloid A
1-acid glycoprotein
Fibronectin
Ferritin
Angiotensinogen

Table 2 Some components of the acute phase response
Neuroendocrine changes
Fever, somnolence, and anorexia
Increased secretion of CRH, corticotropin, cortisol
Increased secretion of arginine vasopressin
Decreased insulin-like growth factor 1 production
Increased adrenal secretion of catecholamines
Hematopoietic changes
Anemia of chronic disease
Leukocytosis
Thrombocytosis
Metabolic changes
Loss of muscle and negative nitrogen balance
Decreased gluconeogenesis
Osteoporosis
Increased hepatic lipogenesis
Increased lipolysis in adipose tissue
Decreased lipoprotein lipase activity in muscle and
adipose tissue
Cachexia
Hepatic changes
Altered synthesis of plasma proteins
Increased metallothionein, inducible nitric oxide
synthase, heme oxygenase, manganese superoxide
dismutase, tissue inhibitor of metalloproteinase-1
Decreased phosphoenolpyruvate carboxykinase activity
Changes in nonprotein plasma constituents
Decreased copper, iron, selenium, and zinc
concentrations
Decreased plasma retinol concentration
Increased glutathione concentration
The APR is a major pathophysiologic phenom-
enon, in which normal homeostatic mechanisms are
replaced by new set points that presumably contribute
to defensive or adaptive capabilities. This latter
likelihood has led to the realization that many of the
changes occurring during the APR are part of the
innate immune response (Medzhitov and Janeway,
2000; Munford and Pugin, 2001).
Several semantic problems are associated with the
APR. The use of this historically based term
occasionally leads to confusion; the APR is not
limited to acute inflammatory states, but may
accompany chronic inflammation as well, resulting
Acute Phase Proteins 3
in what might seem to be an oxymoron, a chronic
APR. Another potential source of confusion is the use
of the term `systemic inflammatory response' to refer
to the APR. The systemic inflammatory response
syndrome (SIRS) has already been defined as the
earliest stage in the continuum of progressive decline
that may occur following severe trauma or sepsis. It is
characterized by high temperature, pulse rate,
respiratory rate, and white cell counts, only one of
which is regarded as part of the acute phase response
(American College of Chest Physicians/Society of
Critical Care Medicine Consensus Conference, 1992).
Finally, a number of investigators have employed
the term `stress response' to refer to the neuroendo-
crine aspects of the APR (Chrousos, 1995). Many of
these investigators have focused on the changes
induced by psychological and emotional stimuli,
often mediated by corticotropin-releasing hormone
and the autonomic nervous system (Sternberg, 1997).
These types of stimuli may also influence other, non-
neuroendocrine components of the APR.
Conditions that commonly lead to an APR include
infection, trauma, surgery, burns, tissue infarction,
various immunologically mediated and crystal-
induced inflammatory conditions, and advanced
cancer. Relatively modest changes occur after
strenuous exercise, heatstroke, and childbirth.
Recent studies have demonstrated that minimal
acute phase protein elevations may be associated
with a large number of conditions not ordinarily
regarded as inflammatory, as discussed below under
Clinical usefulness.
Although multiple components of the acute phase
response often occur together, not all of them occur
uniformly in all patients with varying illnesses. Thus,
discordance between plasma concentrations of differ-
ent acute phase proteins is common. These variations,
which indicate that components of the acute phase
response are individually regulated, may be explained
in part by differences in the patterns of production of
specific cytokines (or their modulators) in different
pathophysiologic states.
REGULATION OF GENE
EXPRESSION
As expected, the same general mechanisms that
govern the regulation of gene expression elsewhere
apply to acute phase protein genes (Brivanlou and
Darnell, 2002). A series of regulatory elements are
bound by transcription factors, which, associated
with coactivators and corepressors, influence chro-
matin structure, the general transcriptional machinery
4 David Samols, Alok Agrawal and Irving Kushner
and RNA polymerase II. However, in-depth studies
of the molecular mechanisms that mediate the effects
of cytokines on expression of individual AAP genes,
as do in-depth studies of many genes, continue to
reveal novel mechanisms by which gene regulation is
accomplished. Examples, described in detail below,
include a mechanism by which rel p50 enhances
Schreiber, 1986), while translational mechanisms
have not been found (Schreiber et al., 1986).
Posttranscriptional mechanisms may participate as
well, as has been shown for SAA and several other
APPs (Jiang et al., 1995; Longley et al., 1999). Indeed,
some cytokines, notably IL-1, have been shown to
influence the stability of mRNAs in several systems
C/EBP functional effects on the CRP gene in the (Winzen et al., 1999; Holtmann et al., 2001).
absence of p65, an effect of steroids on fibrinogen
induction in the absence of a GRE, a requirement for
STAT3 in the response of acute phase SAA to LPS or
IL-6 in the absence of a defined STAT response
C/EBP and rel protein effects on
element and displacement mechanisms whereby one APP gene expression
transcription factor is replaced by another at an
overlapping site. The transcription factors that mediate enhanced
expression of acute phase proteins in response to IL-
6, IL-1, and TNF typically include C/EBP family
Inducers of acute phase gene
expression
Although a wide variety of cytokines, growth factors,
hormones, and other mediators have been found to
influence the expression of acute phase protein genes
in liver or liver-derived cells in culture, the major
stimuli for induction of acute phase changes are the
inflammation-associated cytokines. These molecules
contribute to the inflammatory process at inflamma-
tory sites largely by paracrine or autocrine mechan-
isms, while induction of APP changes results from
bloodborne effects upon hepatocytes. Of these
cytokines, members of the IL-6 family, TNF, IL-1,
members (C/EBP and C/EBP), STAT proteins
(STAT1, STAT3 and STAT5), rel family members
(typically NFB), HNF1, Sp1 and AP-1. Regulatory
elements identified in early studies of acute phase gene
promoter regions as acute phase or IL-6 response
elements have since been defined. Thus, the original
consensus `IL-6RE sequence' (IL-6RE), is now
recognized as a C/EBP-binding motif (Koj, 1996),
while the subsequently defined `acute phase response
element' (APRE), is a binding site for STAT proteins
(Wegenka et al., 1994; Ripperger et al., 1995).
Baumann and Gauldie (1990) proposed that the
major acute phase genes be divided into two classes,
depending on whether or not they responded to IL-1, in
addition to responding to IL-6. Although probably not
TGF, and IFN
have been studied in some detail. precisely accurate in detail, as each acute phase gene
IL-6 is the major stimulator of most acute phase
proteins (Gauldie et al., 1987), while the other
implicated cytokines influence subsets of acute
phase proteins. The effects of these cytokines are
influenced by circulating modulators of cytokine
function, such as IL-1 receptor antagonist (IL-1Ra)
and soluble TNF receptors, which inhibit the effects
of their cognate cytokines, and by soluble IL-6
receptors, which enhance the effects of IL-6. In
addition, other inflammation-associated cytokines
such as IL-4 and IL-10, which have general anti-
responds to a specific set of stimuli employing a unique
combination of regulatory elements and transcription
factors, this classification has provided a useful
framework in which to analyze APP responses to
cytokines. Class I (IL-1-responsive) genes include the
SAA genes, CRP, 1-acid glycoprotein (AGP), C3, and
rat haptoglobin. The promoters of all these genes
contain binding sites for members of the C/EBP and rel
families, often in close proximity (Poli, 1998). While all
members of the C/EBP family bind to similar sequences
(Lamb and McKnight, 1991; Osada et al., 1996), it is
inflammatory effects, inhibit induction of some acute
phase proteins (Loyer et al., 1993; Vasse et al., 1996;
Gabay et al., 1999). Finally, other circulating
mediators such as HGF, insulin, EGF, CSFs, and
glucocorticoids may influence the response to
cytokines.
While mediators capable of induction could
C/EBP and C/EBP isoforms of this family that are
usually activated in association with inflammatory
events. One or both of the C/EBP- or NFB-binding
sites (called B sites) appear to be critical for full
induction of class I genes in response to IL-6 and IL-1
(Prowse and Baumann, 1989; Wilson et al., 1990; Betts
et al., 1993; Cha-Molstad et al., 2000). IL-1 is known to
theoretically alter gene expression by translational, activate rel proteins and C/EBP (Isshiki et al., 1990),
posttranscriptional, or transcriptional mechanisms, it among others. IL-6 can activate C/EBP and can
is transcriptional changes that are thought to account induce new synthesis of C/EBP (Alam et al., 1992;
for most acute phase protein changes (Birch and Cantwell et al., 1998).

Interaction between rel and C/EBP families of
transcription factors may account, in part, for the
synergy often observed between IL-1 and IL-6 in this
class of genes (Xia et al., 1997). In the best-studied
example, the acute phase SAA genes, both IL-6 and
IL-1 alone modestly induce expression, but their
combination is markedly synergistic. This can be
Acute Phase Proteins 5
STAT protein effects on
APP gene expression
A number of class II acute phase genes, specifically
the three chains of fibrinogen, 1-protease inhibitor,
rat thiostatin, and rat 2M, are much more dependent
attributed to activation of C/EBP by IL-6, activa- on STAT3 activation than are class I genes. These
tion of NFB by IL-1 and physical interactions genes often have multiple STAT-binding sites that are
between RelA (p65) and C/EBP, since the binding
sites for these transcription factors are closely spaced
(Li and Liao, 1992; Betts et al., 1993; Ray et al., 1995;
Xia et al., 1997).
In contrast, in Hep3B cells, IL-1 alone has no
effect on CRP expression, but markedly enhances
CRP induction by IL-6. Studies of CRP induction in
this cell line reveal that rel proteins also participate,
critical for their induction, and may lack C/EBP-
binding sites. Since IL-6, but not IL-1, is the major
activator of STAT3, it is not surprising that these
genes are not induced by IL-1. In contrast to many
acute phase genes, IL-1 represses basal and IL-6-
induced transcription of the fibrinogen genes, perhaps
because many putative B sites overlap STAT3-
binding sites (APREs) (Zhang and Fuller, 2000). Such
but in a novel way; an interaction between C/EBP overlapping sites permit competition between NFB
and rel p50 in a region where their binding sites
overlap in the proximal promoter appears to be
critical. For IL-1 effects to be evident, IL-6-induced
transcription factor activation appears to be a
prerequisite and the C/EBP-binding sites in the
promoter region indispensable (Cha-Molstad et al.,
2000; Agrawal et al., 2001).
Participation of C/EBP family members, responsive
to both IL-6 and IL-1, in acute phase protein
induction is of particular interest. C/EBP is
generally downregulated during the acute phase
response (Alam et al., 1992) and C/EBP-containing
dimers on acute phase gene promoters are often
and STAT3; activated NFB may act as a repressor
of fibrinogen transcription by displacing STAT3
(Fuller and Zhang, 2001). Of course, STAT3-binding
sites can also be found in the promoters of class I
genes such as CRP (Zhang et al., 1996), where they
mediate part of the IL-6 response. In this model,
STAT3 cooperates with C/EBP and rel proteins to
affect full induction by IL-6 + IL-1. Although a
STAT3-binding site has not been reported in the
acute phase SAA gene promoters, mice in which the
STAT3 gene was ablated in liver, adipose tissue, and
bone marrow show impaired induction of (class 1)
SAA1 and SAA2, as well as other acute phase genes,
replaced by those composed of C/EBP and C/EBP in response to LPS (Alonzi et al., 2001). Further,
(Poli, 1998). However, mice with a targeted disrup-
tion in the C/EBP gene do not manifest an APR
and do not activate STAT3 in response to LPS.
These data are consistent with a model in which
C/EBP participates indirectly in the APR (Burgess-
ablation of STAT3, the dominant-negative splice
variant of STAT3, led to overexpression of many
acute phase genes, again indicating that STAT3 is an
important regulator of most if not all acute phase
proteins (Yoo et al., 2002).
Beusse and Darlington, 1998). C/EBP and C/EBP
mRNA accumulation are increased by cytokine ex-
posure in the liver (Takiguchi, 1998). In addition,
Synergistic induction of
existing C/EBP is activated by cytokines to trans- APP gene expression
locate from the cytosol to the nucleus. There is
conflicting evidence on the role of phosphorylation of More than additive responses, synergy, in cytokine-
C/EBP and C/EBP as a mechanism for their induced APP gene expression, is most likely due to
activation (Roesler, 2001). In hepatocytes, phos- transcription factor interactions. Most of the known
phorylation of C/EBP following TNF exposure is examples of synergy involve rel protein interactions
associated with its translocation from the cytoplasm with other transcription factors. This is the case
to the nucleus. On the other hand, in vitro for the acute phase SAA genes (Betts et al., 1993;
phosphorylated C/EBP does not bind DNA as
well as its unphosphorylated counterpart (Trautwein
et al., 1994). In contrast, phosphorylation has been
associated with both translocation and stronger DNA
binding of C/EBP, after IL-1 treatment, resulting in
repression of the apoliprotein C-III promoter
(Lacorte et al., 1997).
promoter while STAT3 and
Shimizu and Yamamoto, 1994; Xia et al., 1997), CRP
(Cha-Molstad et al., 2000; Agrawal et al., 2001), and C3
(Wilson et al., 1990). For fibrinogen (Fuller and Zhang,
2001) and AGP (Klein et al., 1987), synergy involves
interactions with the glucocorticoid receptor (GR).
STAT3 acts synergistically with GR (Zhang et al.,
1997) on the fibrinogen-
6 David Samols, Alok Agrawal and Irving Kushner

c-Jun (AP-1) interact with it on the 2M promoter sites. Rat SAA1 gene expression in HeLa cells is
(Yoo et al., 2001). All of these interactions probably repressed by a displacement mechanism in which
function through cooperative coactivator binding, NFB and YY1 compete for overlapping binding
although this has been demonstrated thus far only for sites. If YY1 is present, NFB is displaced from its
the coactivator TIF-1 binding to C/EBP and B site, repressing expression from the gene (Lu
GR (Chang et al., 1998). Other transcription factor et al., 1994; Li and Liao, 1999). Following cytokine
interactions include those between C/EBP and Sp1, exposure, YY1 is presumably either not expressed
and between C/EBP and Myb (Takiguchi, 1998).
Finally, STAT3 and AP-1 induce expression of HNF1 AP-2 binds at two sites in the rat SAA1 promoter
(Leu et al., 2001) which is a necessary, constitutively
active transcription factor that facilitates and is
required for the expression of many acute phase and
other liver genes. Thus, part of the synergistic responses
to cytokines of some acute phase genes may reflect
promoter
changes in HNF1 levels.
Glucocorticoids are generally positive effectors of
acute phase gene expression in hepatocytes, although
their effects are minimal in the absence of cytokines.
Glucocorticoid action can be direct or indirect.
Some acute phase genes contain well-defined gluco-
corticoid response elements (GRE) in their promo-
ters. Examples include AGP (Baumann and Maquat,
or expressed at low levels in hepatocytes. Similarly,
and can also repress transcription by displacing
NFB (Ren and Liao, 2001). As described above
(Zhang and Fuller, 1997), competition between
STAT3 and NFB for binding to a critical IL-6-
response element in the fibrinogen-
explains the inhibitory effect of IL-1 on fibrinogen
expression. While C/EBP, NFB, and AP-2 are
known to activate transcription, as indicated above,
they can all also act as repressors, depending on the
context.
Despite the presence of repression mechanisms,
extra-hepatic synthesis of acute phase protein genes
is abundantly documented (Aldred et al., 1992).
1986), fibrinogen- and fibrinogen- (Fuller and
Zhang, 2001). In others, glucocorticoids apparently
act indirectly and provide general support. In the case
of the fibrinogen-
gene, which has no recognizable not responsive to IL-1 + IL-6 (Tucker and Sack,
GREs in its promoter sequence, it has been
proposed that the glucocorticoid receptor interacts
with STAT3 either by physical interaction or
through a coactivator when STAT3 is bound to an
APRE (Zhang et al., 1997; Fuller and Zhang, 2001).
In addition to the well-characterized transcription
Often these genes are regulated by different mechan-
isms than those acting in hepatocytes. Thus, in
contrast to hepatocytes, brain expression of SAA1 is
2001). Aortic smooth muscle cell expression of
the acute phase SAA genes does not occur in the
absence of glucocorticoids (Kumon et al., 2001) and
synovial cell expression of SAA1, unlike hepatocytes,
involves cooperation between SP1 and SAF (Ray
et al., 1999). In intestinal expression of AGP, it is
factors described above, less well-characterized
factors have been shown to participate in acute
phase gene regulation. A factor designated SAF has
been described which participates in regulation of
acute phase SAA genes. It also regulates fibrinogen-
CRP expression has been reported in several other
through interactions with the ubiquitous transcrip-
tion factor Sp1 (Ray and Ray, 1997; Ray, 2000). A
mitochondrial DNA-binding protein, P16, has
been reported to bind to a cis-element in the
fibrinogen- promoter (Liu et al., 1997) and a
constitutive factor, SAA3 enhancing factor (SEF),
has been shown to participate in murine SAA3
expression. It has been suggested that SEF affects the
promoters of other acute phase genes as well (Bing
et al., 1999).
Negative and extra-hepatic
regulation of APP gene expression
Repression of acute phase protein gene expression
has also been reported, particularly at extra-hepatic
TGF, rather than IL-1 or IL-6, that induces C/EBP
isoforms (Yoo et al., 2001). Activation of Src and
STAT3 has been shown to participate in CRP
expression in fibroblasts (Turkson et al., 1998).
tissues outside the liver, including neurons (Yasojima
et al., 2000), atherosclerotic plaques (Yasojima et al.,
2001), lacrymal glands (Wei et al., 2001), and
mononuclear cells (Murphy et al., 1991). The
mechanisms underlying CRP expression in these
sites are as yet unexplained.
FUNCTIONS OF ACUTE PHASE
PROTEINS
Discussion of the function of the APR must be
tempered by several caveats. First, we presume that
acute phase changes play a beneficial role in
adaptation and defense that they are part of the
innate immune response because we are inclined to
believe that nature tries to accomplish useful

purposes. This is not necessarily true. The host
response may be either protective or detrimental;
maladaptive sequelae of the inflammatory response
such as the SIRS, described above, multiple organ
failure and death may occur (Dhainaut et al., 2001;
Marshall, 2001). Second, our presumptions about the
functions of acute phase proteins are largely based on
their known functional capabilities in vitro and on
logical speculation as to how these may serve useful
purposes. We are not always certain that these
presumptions are valid in in vivo situations. Finally,
we must bear in mind that many of these molecules
are multifunctional and may participate in the innate
immune response, or in adapting to it, in more than
one way, including ways we are not yet aware of.
With these reservations in mind, it is appropriate to
adduce functional roles for many acute phase
proteins, either in enhancing or in restraining some
of the complex cascades and interactions that occur in
inflammatory states (Kushner, 1998), or in adapting
to the perturbations in metabolism that occur during
these states. APPs are felt to participate in a variety of
inflammation-related activities, such as killing or
limiting dispersion of pathogens, protecting the host
from destructive elements of the inflammatory
response (e.g. inhibition of proteases) and repair of
tissue damage. Some APPs are directly harmful to
microbes, while others target sites for cellular
responses. Some work alone while others participate
in cascades. An overview of the probable roles of APP
can be gained by citing several examples, beginning
with CRP, SAA, and AGP.
CRP is a good example of why simple classification
of acute phase proteins as either pro- or anti-
inflammatory may not be valid. A very large number
of binding specificities and biologic effects of CRP
have been reported (Mortensen, 2001; Volanakis,
2001). A major function of CRP is presumed to be
`proinflammatory', related to its ability to specifically
bind to phosphocholine and to some nuclear
components. It can thus recognize some foreign
pathogens as well as both phospholipid and nuclear
constituents of damaged or necrotic cells. Further,
when bound to one of its ligands, CRP can activate
the complement system by the classical pathway.
CRP may also interact with Fc receptors on
phagocytic cells and act as an opsonin (Bharadwaj
et al., 1999; Hundt et al., 2001). These findings
suggest that CRP plays a proinflammatory role by
initiating elimination of targeted bacteria or cells by
interaction with humoral and cellular effector systems
of inflammation. Indeed, protection from lethal
bacterial infection has been observed in transgenic
mice expressing CRP (Volanakis, 2001; Szalai, 2002).
A proinflammatory role for CRP is further supported
Acute Phase Proteins 7
by the observation that CRP can induce production
of inflammatory cytokines (Ballou and Lozanski,
1992) and tissue factor (Cermak et al., 1993) by
monocytes, as well as inducing shedding of IL-6
receptors by polymorphonuclear leukocytes (Jones
et al., 1999). In addition, CRP has been found to
induce adhesion molecule expression in endothelial
cells in the presence of serum (Pasceri et al., 2000) and
to bind to degraded low-density lipoprotein with
subsequent complement activation (Bhakdi et al.,
1999).
In contrast, studies of the effects of CRP on
chemotaxis, phagocytosis, and respiratory burst
activity of phagocytic cells suggest a significant anti-
inflammatory role. CRP has been reported to inhibit
neutrophil chemotaxis, to inhibit superoxide genera-
tion by neutrophils (Foldes-Filep et al., 1992;
Shephard et al., 1992), and to induce large amounts
of IL-1Ra in peripheral blood mononuclear cells
(Tilg and Peschel, 1996). Anti-inflammatory effects
could result from the ability of CRP to cause
enhanced shedding of L-selectin (Zouki et al., 1997).
Recently, CRP has been shown to bind to apoptotic
lymphocytes, with consequent anti-inflammatory
effects (Gershov et al., 2000). CRP can bind factor
H, with consequent inhibition of the alternative
complement pathway and a diminished inflammatory
response (Jarva et al., 1999). Finally, studies in
transgenic mice, in which CRP is protective against
complement-induced alveolitis (Webster et al., 1994)
and endotoxemia (Xia and Samols, 1997) suggest that
the net effect of CRP in vivo is anti-inflammatory
(Ahmed et al., 1996). Taken together, these data
suggest that CRP may play multiple roles in the
course of inflammatory processes.
The primary physiological function of SAA, the
other major human acute phase protein, similarly
remains elusive. SAA has been shown to induce
adhesion and chemotaxis of phagocytic cells and
lymphocytes (Xu et al., 1995) acting through formyl
peptide receptors (Su et al., 1999; Le et al., 2001). It is
also reported to induce cytokine production (Patel
et al., 1998) and metalloproteinase secretion (Migita
et al., 1998). In addition, the findings that macro-
phages bear specific binding sites for SAA and
that SAA-rich high-density lipoproteins display
increased ability to transfer cholesterol to macro-
phages at inflammatory sites suggest a role of SAA in
transfer of cholesterol to inflammatory cells
(Lindhorst et al., 1997; Artl et al., 2000). SAA has
also been reported to enhance low-density lipoprotein
oxidation in arterial cell walls (Berliner et al., 1995).
Finally, SAA3 produced by rabbit synovial fibro-
blasts induces synthesis of collagenase (Mitchell et al.,
1991).
8 David Samols, Alok Agrawal and Irving Kushner
A number of protective and anti-inflammatory
effects of AGP have been reported. AGP binds to
bacterial endotoxin and protects mice from endo-
toxin-induced septic and hypovolemic shock (Moore
et al., 1997; Muchitsch et al., 1998). Transgenic mice
overexpressing AGP are protected from Klebsiella
pneumoniae infection, suggesting a role in nonspecific
resistance to infection (Hochepied et al., 2000). Anti-
inflammatory effects of AGP include inhibition of
neutrophil activation and modulation of lymphocyte
responsiveness (Williams et al., 1997). AGP interacts
with plasminogen activator inhibitor type 1 and
stabilizes its inhibitory activity (Boncela et al., 2001).
Finally, AGP exerts anti-apoptotic and anti-inflam-
matory effects in ischemia/reperfusion injury and
some murine models of TNF toxicity (Van Molle
et al., 1999; Daemen et al., 2000).
Complement system members
Complement components, most of which have been
found to be APPs, are long-recognized opsonins and
mediators of the inflammatory response (Cooper,
1999). Activation of the complement system results
RI
in generation of three anaphylotoxins, C3a, C4a, and
C5a, which can induce vascular permeability and
smooth muscle contraction in blood vessels and lead
to release of histamine and other vasoactive
substances. C5a is also a chemotaxin and induces
phagocytic cells to secrete inflammatory mediators,
aggregate, and adhere to surfaces. Finally, activation
of terminal complement components generates the
membrane attack complex, a series of proteinprotein
interactions involving C5C9, with lysis of target
pathogens.
Mannan-binding lectin (MBL) is an APP that
initiates one of the three independent complement
activation pathways and is an important component
of innate immunity (Petersen et al., 2001). It binds to
a wide range of pathogenic bacteria, viruses, fungi,
and parasites as a result of its predefined lectin
specificity, with consequent initiation of comple-
ment activation through complexed MBL-associated
proteases.
Participants in inflammatory
responses
Lipopolysaccharide (LPS)-binding protein (LBP), an
important participant in innate immunity, facilitates
interaction between LPS and its receptor CD14 on
phagocytic cells (Hailman et al., 1994; Schumann
et al., 1996). The lipid A portion of LPS binds to LBP
in plasma and is delivered to the cell surface receptor
CD14, where it is transferred to toll-like receptor 4
(TLR4), capable of transmembrane signaling through
its accessory protein MD2. Rapid activation of an
intracellular signaling network (similar to the signal-
ing systems of IL-1 and IL-18) ensues, with resultant
induction of many genes encoding inflammatory
mediators such as cytokines, adhesion molecules, and
tissue factor, as well as to activation of neutrophils
(Alexander and Rietschel, 2001; Guha and Mackman,
2001). Non-CD14-bearing cells, such as endothelial
cells, can also respond to LPS through this pathway
via the soluble form of CD14, an interaction that is
similarly enhanced by LBP. It has been proposed that
LBP can also facilitate neutralization of LPS under
certain conditions (Lamping et al., 1998).
Granulocyte colony-stimulating factor (G-CSF)
stimulates proliferation and differentiation of hema-
topoietic cells and is the principal growth factor
regulating maturation, proliferation, and differentia-
tion of neutrophil precursors (Aritomi et al., 1999). In
addition to this obviously proinflammatory function,
G-CSF can stimulate superoxide production
(Lindemann et al., 1991) and expression of Fc-
(Kerst et al., 1993) in neutrophils. G-CSF phosphor-
ylates a Cu/Zn-SOD through receptor-associated
kinases, diminishes Cu/Zn-SOD levels and activity
(Csar et al., 2001) and enhances antibody-dependent
cytotoxicity (Stockmeyer et al., 2001). In contrast, IL-
1Ra is an APP of hepatic origin that binds avidly to
IL-1 receptors with no apparent agonist function,
thus inhibiting the effects of IL-1. It is presumed
that the functional role played by this, and the many
other `anti-inflammatory' molecules that are pro-
duced early in the course of inflammatory states
(Gabay et al., 1997b; Tanuma et al., 1997), is to
modulate the effects of potentially deleterious
proinflammatory processes.
Coagulation system
It is not surprising that a number of proteins of the
coagulation and fibrinolytic systems are APPs, in
light of the phylogenetically ancient association
between coagulation and inflammation; invertebrates
possess a `common cellular and humoral pathway of
inflammation and clotting' in response to trauma or
infection (Opal, 2000). In recent years, there has been
increasing recognition that molecules involved in
regulation of hemostasis also influence inflamma-
tory pathways (Esmon, 2001; van der Poll, 2001).
Fibrinogen is an excellent example: a multifunctional
glycoprotein that plays important, overlapping roles

in hemostasis, inflammation, and wound healing
(Clark, 2001; Mosesson et al., 2001). In addition to
participating in formation of clots, it stimulates
secretion of chemokines by macrophages (Smiley
et al., 2001). Treatment of neutrophils with fibrinogen
in the presence of formyl-methionyl-leucyl-phenyla-
lanine or leukotriene B4 results in increased IL-8
synthesis (Kuhns et al., 2001). Binding of fibrinogen
to leukocyte integrins has been shown (Ugarova and
Yakubenko, 2001) and it has been reported that
fibrinogen is an important antioxidant (Kaplan et al.,
2001).
Antiproteases and transport proteins
Both antiproteases and the transport proteins (which
manifest antioxidant activity) can be presumed to
protect the host against potentially harmful com-
ponents of the inflammatory response. Inflammation
involves both release of proteases from phagocytic
cells and activation of serum proteases, as well as
generation of potentially toxic reactive oxygen
species. Thus, 1-proteinase inhibitor (1-PI) (also
called 1-antitrypsin) can inactivate a large number of
serine proteases, but its major function appears to be
to inhibit neutrophil elastase. In addition, it can
inhibit neutrophil cathepsin G and proteinase 3, as
well as mast cell proteinase II (Stockley, 2001). The
critical role played by of some of these proteases in
destruction of bacteria within neutrophils has recently
been established (Reeves et al., 2002). It stands to
Acute Phase Proteins 9
not only participates in control of the classic
complement activation pathway, but also inhibits
kallikrein, an enzyme that contributes to inflamma-
tion by generating bradykinin and by amplifying the
intrinsic pathway of coagulation (Caliezi et al., 2000).
Ceruloplasmin (Cp), originally described as a
copper transport molecule, is a multifunctional
enzyme and a multifunctional protein (Floris et al.,
2000) which plays essential roles in both iron and
copper metabolism and integrates these metabolic
pathways (Mzhel'skaya, 2000). Its major role during
the APR may be to act as an antioxidant, due largely
to its ferroxidase activity. Cp plays an important role
in mobilization and oxidation of iron from tissue
stores, with subsequent incorporation of ferric iron
into transferrin, thus preventing the generation of
reactive oxygen species. In addition, it can inactivate
reactive oxygen species such as superoxide and
hydrogen peroxide (Halliwell and Gutteridge, 1990).
Finally, Cp modulates the function of endothelial
nitric oxide synthase and thus controls NO-dependent
relaxation of the vasculature (Bianchini et al., 1999).
Haptoglobin (Hp) binds circulating hemoglobin
liberated as a result of intravascular hemolysis, with
consequent clearance of the complexes thus formed
by cellular receptors (Kristiansen et al., 2001). In this
way, it inhibits free-hemoglobin-induced lipid perox-
idation (Halliwell and Gutteridge, 1990) and protects
kidneys from damage. Hp knockout mice are more
sensitive than wild-type mice to phenylhydrazine-
induced hemolysis, supporting its protective role
during hemolysis (Lim et al., 2000). In addition, Hp
reason that acute phase antiproteases serve to limit
the activity of these powerful enzymes when they
escape to the extracellular milieu. Like AGP, 1-PI
has been reported to exert anti-apoptotic and anti-
inflammatory effects in murine models of ischemia/
reperfusion injury and in a model of TNF/
galactosamine toxicity (Van Molle et al., 1999;
Daemen et al., 2000). Finally, 1-PI inhibits
neutrophil superoxide production and induces
macrophage-derived IL-1Ra (Bucurenci et al., 1992;
Tilg et al., 1993).
Similarly, 1-antichymotrypsin (1-ACT) strongly
inhibits neutrophil cathepsin G and mast cell
chymase. An additional anti-inflammatory role is
suggested by the finding that 1-ACT inhibits the
activity of the macrophage cell surface enzyme that
facilitates conversion of pro-macrophage-stimulating
protein (pro-MSP) to active MSP (Skeel and
Leonard, 2001). Both 1-PI and 1-ACT prevent
degradation of extracellular matrix proteins caused
by cell-derived proteinases, permitting cell attachment
and spreading (Ikari et al., 2001). Another serpin, C-1
inhibitor (listed in Table 1 under complement system)
binds to the -2 integrin Mac-1, as does fibrinogen,
suggesting that these APPs might regulate Mac-1-
dependent cell function. (El Ghmati et al., 1996).
Hemopexin (Hx) is also felt to prevent oxidative
damage. It binds free heme, which like hemoglobin, is
capable of producing peroxidation (Gutteridge and
Smith, 1988). In addition, Hx strongly inhibits the
stimulatory effect of heme on growth of Bacteroides
fragilis, an anaerobic pathogen (Rocha et al., 2001),
and activates a number of genes that encode proteins
important for cellular defenses against oxidative
stress, such as heme oxygenase-1 and the cysteine-
rich metallothioneins (Sung et al., 2000).
In summary, the presumed functions of APPs affect
many aspects of the innate immune response, and
consequent inflammation, including cytokine
responses, coagulation, inflammatory cell behavior,
vascular alterations and complement activation.
APPs may protect against degradative enzymes and
oxidative processes and may contribute to wound
healing. In addition, they may affect metabolic
behavior during illness and ultimately, influence the
subsequent adaptive immune response.
10 David Samols, Alok Agrawal and Irving Kushner
CLINICAL USEFULNESS
Determination of serum (or plasma) concentrations
of APPs is useful to clinicians, since they reflect the
presence and intensity of inflammatory processes
(Gabay and Kushner, 1999). Although they lack
diagnostic specificity, levels of APPs are helpful in
differentiating inflammatory from noninflammatory
conditions and in guiding patient management during
the course of inflammatory diseases. Finally, higher
concentrations of APPs indicate a poor prognosis in a
wide variety of conditions, including rheumatoid
arthritis, various malignancies, diabetes mellitus, and
uremia.
Currently, the most widely used indicators of the
APP response are the erythrocyte sedimentation rate
(ESR) and serum CRP concentration. The rate at
which erythrocytes fall through plasma, the ESR,
generally reflects degree of inflammation. It is
influenced by both known and unknown factors but
correlates moderately well with plasma concentra-
tions of the APP fibrinogen (Bedell and Bush, 1985).
The ESR has the advantages of familiarity, simplicity,
and an abundant literature compiled over nearly eight
decades. However, ESR values are imprecise and
sometimes misleading, since they are only an indirect
measure of APP concentrations and can be greatly
influenced by the size, shape, or number of
erythrocytes, by other plasma constituents such as
monoclonal immunoglobulins, by age and by
unknown factors. In contrast, CRP levels reflect
synthesis of a single acute phase protein, directly
measured, whose concentration changes much more
rapidly in response to worsening or improvement in
the inflammatory process than does the ESR and
which is only minimally influenced by the subject's
age and sex (Wener et al., 2000).
Multiple components of the APR commonly, but
not invariably, occur together. Discordance between
concentrations of different APPs in different
diseases and different patients is not uncommon;
some APPs may be elevated while others are not. For
example, many patients with active systemic lupus
erythematosus have elevated ESR, but normal CRP
concentrations. These patients are, however, capable
of mounting a CRP response, as shown by marked
increases in CRP concentrations during bacterial
infection. Such variations in APPs, which indicate
that components of the APR are individually
regulated, may be explained, at least in part, by
differences in production of specific cytokines or their
modulators in different diseases. Accordingly, it
appears safe to say that there is no single best
laboratory test to reflect inflammation. Many
clinicians measure several acute phase reactants,
rather than employing a single test, and interpret
them in light of the clinical context.
Most normal subjects have CRP concentrations of
2 mg/L or less, but some have concentrations as high
as 10 mg/L. The latter finding, long attributed to
modest stimulation by minimally apparent, low-grade
inflammatory processes such as gingivitis, or by trivial
injury incurred in the course of daily living, has led
to the suggestion that values should be over 10 mg/L
to be regarded as clinically significant (Morley and
Kushner, 1982; Macy et al., 1997). However, recent
data indicate that the finding of CRP concentrations
between 2 and 10 mg/L may have some clinical
relevance. Most commonly employed laboratory
assays for CRP are not sensitive in this range; a `high
sensitivity' CRP assay is required (Conti, 2001).
The interpretation of such a minimal APR has
recently become a subject of considerable interest.
Minimally elevated APPs, including CRP, are asso-
ciated with the progression of atherosclerosis. They
predict the risk of a first myocardial infarction
among apparently healthy individuals and are asso-
ciated with a worse prognosis among patients with
stable and unstable angina (Haverkate et al., 1997;
Ridker et al., 1997). In the elderly, elevated levels of
acute phase proteins predict `failure to thrive' and even
increased mortality (Harris et al., 1999). A possible
explanation for this phenomenon is, of course, that
these individuals have an ongoing inflammatory
process, in coronary arteries or elsewhere.
However, CRP values in this range are associated
with a large number of states not ordinarily regarded
as inflammatory. Among these conditions are obesity,
poor physical conditioning, high protein diet, depres-
sion and notably high or low alcohol intake (Fleming,
2000; Geffken et al., 2001; Imhof et al., 2001;
Kushner, 2001). It may be that minimally elevated
acute phase protein levels merely identify individuals
who bear an increased burden of tissue damage
resulting from cumulative oxidative stress, a process
strongly implicated in the pathogenesis of aging
(Kushner, 2001). Such individuals are biologically
(not necessarily chronologically) older and as such,
would be expected to have a greater likelihood of
disease or death. In addition, recent data indicate that
baseline CRP levels are heritable and that a promoter
polymorphism of the IL-6 gene (-174G/C) is
associated with high CRP levels (Vickers et al.,
2002). At present, it is far from clear that high
sensitivity CRP screening to identify individuals at
risk for atherosclerosis, as some suggest (Ridker et al.,
2001), will prove to be an effective procedure
(Campbell et al., 2002; Kushner, 2002).

Currently, other acute phase reactants are rarely
employed clinically. SAA concentrations usually
parallel those of CRP. Although SAA is probably a
more sensitive marker of inflammatory disease (Malle
and De Beer, 1996), assays for SAA are not widely
available at present. In addition, a high degree of
sensitivity is not always desirable in the clinical
setting, because of attendant loss of specificity. While
plasma concentrations of cytokines and cytokine
receptors have been studied in patients with
inflammatory conditions, quantitation of cytokines
presents several problems, partly because of their
short plasma half-lives and the presence of blocking
factors (May et al., 1988; Arend et al., 1994). Reports
of different patterns of cytokine responses in different
diseases suggest that cytokine determinations may
ultimately have diagnostic value (Gabay et al., 1994,
1997a), as does the report that IL-6 is more sensitive
than ESR for indicating disease activity in giant cell
arteritis (Weyand et al., 2000). However, until further
studies are available, high cost, limited availability,
and absence of standardization will retard measure-
ment of plasma cytokines and their receptors in
clinical practice.
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