Alpha-1-acid glycoprotein

Biochimica et Biophysica Acta 1482 (2000) 157^171 www.elsevier.com/locate/bba

Review

Alpha-1-acid glycoprotein Thierry Fournier a , Najet Medjoubi-N b , Dominique Porquet

b;

*

a

b

INSERM U427, Faculte¨ des Sciences Pharmaceutiques et Biologiques, Universite¨ Paris 5 Rene¨ Descartes, Paris, France Laboratoire de Biochimie Ge¨ne¨rale, EA 1595, UFR de Pharmacie, 5 rue J.B. Cle¨ment, 92296 Chatenay-Malabry, cedex, France Received 19 October 1999; received in revised form 21 January 2000; accepted 8 February 2000

Abstract Alpha-1-acid glycoprotein (AGP) or orosomucoid (ORM) is a 41^43-kDa glycoprotein with a pI of 2.8^3.8. The peptide moiety is a single chain of 183 amino acids (human) or 187 amino acids (rat) with two and one disulfide bridges in humans and rats,respectively. The carbohydrate content represents 45% of the molecular weight attached in the form of five to six highly sialylated complex-type-N-linked glycans. AGP is one of the major acute phase proteins in humans, rats, mice and other species. As most acute phase proteins, its serum concentration increases in response to systemic tissue injury, inflammation or infection, and these changes in serum protein concentrations have been correlated with increases in hepatic synthesis. Expression of the AGP gene is controlled by a combination of the major regulatory mediators, i.e. glucocorticoids and a cytokine network involving mainly interleukin-1L (IL-1L), tumour necrosis factor-K (TNFK), interleukin-6 and IL-6 related cytokines. It is now well established that the acute phase response may take place in extra-hepatic cell types, and may be regulated by inflammatory mediators as observed in hepatocytes. The biological function of AGP remains unknown ; however,a number of activities of possible physiological significance, such as various immunomodulating effects, have been described. AGP also has the ability to bind and to carry numerous basic and neutral lipophilic drugs from endogenous (steroid hormones) and exogenous origin ; one to seven binding sites have been described. AGP can also bind acidic drugs such as phenobarbital. The immunomodulatory as well as the binding activities of AGP have been shown to be mostly dependent on carbohydrate composition. Finally, the use of AGP transgenic animals enabled to address in vivo, functionality of responsive elements and tissue specificity, as well as the effects of drugs that bind to AGP and will be an useful tool to determine the physiological role of AGP. ß 2000 Elsevier Science B.V. All rights reserved. Keywords: K1-Acid glycoprotein; Orosomucoid ; Structure; Gene expression; In£ammation; Function

1. Introduction Alpha-1-acid glycoprotein (AGP) or orosomucoid was concomitantly ¢rst described in 1950 by Karl Schmid [1,2] and Richard J. Winzler and colleagues [3], and turned out to be a very unusual protein: a very low pI of 2.8^3.8 and a very high carbohydrate

* Corresponding author. Fax: +33-1-4003-4790; E-mail: [email protected]

content of 45%. For about 30 years, AGP was considered to be the protein with the highest carbohydrate content. In 1980, galactoglycoprotein that had a carbohydrate moiety of 76% was described [4,5]. Although numerous articles were devoted to AGP since 1950, its exact biological function remains obscure. However, numerous activities of potential physiological signi¢cance have been described, such as various immunomodulating e¡ects, the ability to bind basic drugs and many other molecules like steroid hormones, the latter leading to the suggestion

0167-4838 / 00 / $ ^ see front matter ß 2000 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 7 - 4 8 3 8 ( 0 0 ) 0 0 1 5 3 - 9

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that AGP might be a member of the lipocalin family. In addition, AGP serum concentrations that remain stable in physiological conditions (about 1 g/l in humans and 0.2 g/l in rats) increase several-fold during acute-phase reactions and AGP is considered as a major member of the positive acute phase protein family. In this chapter, we will focus on: (1) the AGP protein and corresponding gene structures; (2) the regulation of its hepatic as well as extra-hepatic expression; and (3) the biological functions of AGP. 2. AGP protein and gene structures 2.1. AGP structure Human AGP is a glycoprotein of 41^43 kDa in molecular weight, which consists approximately of 45% carbohydrate [6] attached in the form of ¢ve complex-type N-linked glycans [7]. AGP has been crystallised as the Pb2‡ salt in the form of hexagonal bipyramids [2]. An unusually high solubility (in water and in many polar organic solvents) is another notable characteristic of AGP. Di¡erent forms of AGP can be distinguished in serum depending on the type of glycosylation and multiple amino acid substitutions. The protein is a single polypeptide chain of 183 amino acids. A 22 amino acid di¡erence was detected between the two variants of AGP (ORM1 and ORM2) [8] encoded by two di¡erent genes (see below). In addition, at position 32 and 47, other amino acids can be present, probably re£ecting polymorphism in the human population. Signi¢cant degrees of homology were found between AGP and human IgG [9] as well as between AGP and the EGF-binding domain of EGF receptor [10]. The carbohydrate part of AGP has been thoroughly investigated because this is one of the few serum glycoproteins that contains tetra-antennary as well as di- and tri-antennary N-linked glycans. Indeed, each of the N-glycosylation sites of AGP (Asn-15, -38, -54, -75, -85) can express any of the glycans shown in Fig. 1, corresponding to di¡erent degrees of branching (di-antennary versus tri- or tetra-antennary glycans). Moreover, the terminating sugars on glycan chains are responsible for a great deal of the diversity found on glycans. Neuraminic

acid (NeuAc) is one of the common terminating sugars (10^12% of the whole sugars, giving rise to a very low pI of 2.8^3.8); it can be linked in either an K2^3 or K2^6 linkage to galactose. Fucose is another terminating sugar, which can be linked K1^3 to GlcNAc on an external branch, as well as K1^6 to the core GlcNAc and K1^2 to Gal. Thirty % of human control serum does not contain fucose at all, and high degree of fucosylation is associated with a low content or a total absence of di-antennary glycans and with a high content of tri- and/or tetra-antennary glycans. Theoretically, this high diversity of structure would give rise to more than 105 di¡erent glycoforms of AGP, each bearing a unique combination of glycans at the ¢ve-glycosylation sites. In fact, this does not occur because glycosylation site 1 never carries a tetra-antennary glycan, glycosylation site 2 never carries glycans with fucose, glycosylation site 4 never carries a di-antennary glycan, and only glycosylation sites 4 and 5 carry tetra-antennary glycans with more than one fucose. Thus, only 12^20 glycoforms of AGP can be detected in normal human serum and this micro-heterogeneity is strongly dependent on the pathophysiological conditions. For example, substantial increases in glycoforms expressing di-antennary glycans are apparent in the early phase of an acute-phase reaction as well as an increase in the degree of 3-fucosylation. It appears that IL-1, IL-6, TNFK and glucocorticoids are involved in these modi¢cations [11]. Changes in glycosylation of AGP are not restricted to acute in£ammatory conditions, but also occur in a wide variety of other pathophysiological conditions like pregnancy, severe rheumatoid arthritis, alcoholic liver cirrhosis and hepatitis [12^16]. These changes in glycosylation could of course a¡ect the biological properties of AGP. Finally, AGP is desialylated in serum and endocytosis and degradation of asialoAGP are mediated by a liver asialoglycoprotein receptor, the so-called `hepatic binding protein' (HBP) [17]. The rat AGP is a protein of 187 amino acids (mature form) sharing 59% amino acid sequence homology with human AGP and its molecular weight is 40^44 kDa [18]. It contains six N-linked complex type oligosaccharides per molecule [19]. Studies in the rat have been restricted to the quanti¢cation of

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Fig. 1. Di-, tri- and tetra-antennary N-linked complex glycans on human AGP. Man, mannose; GlcNAc, N-acetylglucosamine ; Fuc, fucose; NeuAc, neuraminic acid (sialic acid); Gal, galactose.

di¡erent glycoforms of AGP using a crossed a¤noimmunoelectrophoresis with lectins (mainly concanavalin A, ConA) used as the carbohydrate-binding components in the ¢rst dimension gel, and a polyclonal anti-AGP-IgG used for immunoprecipitation in the second dimension gel. With this technique, changes in rat AGP glycoforms during an in£ammatory reaction were comparable to those found in human [20].

In the case of mouse AGP, two AGP main forms of 187 amino acids were the products of two main AGP genes, AGP-1 and AGP-2 and ¢ve and six potential glycosylation sites have been identi¢ed in AGP-1 and AGP-2, respectively. Four of them are highly conserved in human, rat and mouse (position 16, 58, 75 and 86 in rodents and 15, 54, 76 and 85 in humans) [21]. Furthermore, two alleles of AGP-1, called AGP-1A and AGP-1B, di¡er by a

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transition at nucleotide 499, which changes an Arg to a Gln. 2.2. Structure of the genes encoding AGP Human AGP is the product of a cluster of three adjacent genes: AGP-A, AGP-B and AGP-BP covering 70 kb of the human genome and located on chromosome 9. AGP-A gene is actively expressed in human liver and codes for the major component of serum AGP (ORM1). AGP-B and AGP-BP are identical, probably as the result of a recent duplication, and expressed at least 100-fold less than AGP-A. They di¡er from the AGP-A gene, as indicated above, by 22 base substitutions, and code for the ORM2 variant of AGP [22]. Only AGP-A can be induced by acute-phase stimuli and su¤cient information for tissue-speci¢city is contained within a 6.6kb segment comprising the whole coding region composed of six exons and ¢ve introns plus a 1.2-kb 5P£anking and a 2-kb 3P-£anking DNA region [23]. Rat AGP corresponds to a single gene from which, nucleotide sequence of messenger RNA was established in 1981 [24] and the complete structure in 1985 [25]. In the BALB/c mouse, as indicated above, two main genes may be arranged as a cluster on chromosome 4 and code the two main forms of AGP, AGP1 and AGP-2 [26]. These genes have an identical structure to the human and rat genes with six exons and ¢ve introns. Furthermore, two allelic variants of AGP-2 (AGP-2A and AGP-2B), corresponding to a DNA polymorphism have been identi¢ed. Several studies have clearly shown that the constitutive level of AGP-1 is much higher (5-fold) than AGP-2 and that the increase in AGP-1 mRNA and not AGP-2 mRNA accounts for most of the change in the mouse AGP mRNA pool size seen during the acute phase response [27]. In 1992, Chang et al. [28] showed that there are three AGP genes in Mus domesticus. The latest gene was called AGP-3. The mouse AGP-3 gene sequence is very similar to that of AGP-2, but two major di¡erences have to be mentioned: AGP-3 lacks 86 nucleotides in intron 1, while AGP-2 has an additional (GT)28 tract in intron 5. This AGP-3 gene is always transcribed at a very low level (two orders of magnitude weaker than AGP-2) and code a protein that di¡ers from the

AGP-2 protein by 45 amino acid substitutions and by the existence of only three potential glycosylation sites. Finally, in another species of mice, Mus caroli, eight AGP genes were characterised, only two of them are expressed [29]. In 1987, Stone and Maurer [30] reported a porcine cDNA nucleotide sequence which is 70 and 59% homologous with the human and rat sequences, respectively. Five potential sites of glycosylation are present in the porcine AGP sequence. An AGP complementary DNA clone has been isolated in 1991 from an RNA acute phase rabbit liver library, by using a RT-PCR technique and primers selected by comparison of AGP conserved sequences in mouse, rat and human [31]. The main and longest cDNA cloned contains a 606 nucleotide-coding region that reveals more than 70% homology with the coding sequence of the human AGP. A translational reading frame from the ¢rst ATG gives rise to a protein of 22 kDa, with a putative signal sequence of 18 amino acids, leading to a putative size of mature rabbit AGP peptide of 20 kDa, containing 194 amino acids. In a second study, Ray and Ray [32], using the AGP cDNA as a probe have screened a rabbit liver EMBL genomic library and isolated the rabbit AGP gene ^ as a region of 4.2 kb organised in six exons and ¢ve introns. 3. AGP hepatic expression and its regulation Alpha-1 acid glycoprotein is one of the plasma proteins synthesised by the liver and is mainly secreted by hepatocytes, although extra-hepatic AGP gene expression has also been reported and will be discussed in the next section. Hepatic production of these proteins, termed the acute phase proteins (APPs), is increased following the response to various stressful stimuli: physical trauma, such as surgery or wounding, bacterial infection, or unspeci¢c in£ammatory stimuli, such as subcutaneous injection of turpentine [33,34]. These positive acute phase proteins can be divided into two major classes depending on the response to cytokines. Type 1 APPs, including AGP, complement component 3, serum amyloid A, C-reactive protein, haptoglobin and hemopexin, are regulated by IL-1, IL-6 and glucocorticoids and type

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Fig. 2. Regulatory elements and trans-acting factors implicated in the expression of the AGP gene. The AGP gene promoter contains several positive cis-acting sequences within the SRU that are involved in its regulation by glucocorticoids: the GRE that binds the glucocorticoid receptor interacting with C/EBPL; the upstream responsive elements (URE) and other regions that interact with C/ EBPL. All these elements are essential for maximal induction of the AGP promoter by glucocorticoids. The PBRE and the region probably involved in growth hormone response are located within the SRU, and interact with unknown factors (X factor), NF-UB and C/EBPK factors. The distal responsive element (DRE) implicated in the regulation of AGP by cytokines is located in the enhancer region and interacts with C/EBPL.

2 APP, including the three chains of ¢brinogen and several proteases inhibitors, are regulated by IL-6type cytokines and glucocorticoids [35,36]. AGP is a prominent type 1 APP found in many vertebrate species (human, rats, mice and rabbits), whose plasma concentration increases following systemic tissue injury. The magnitude of change varies from species to species and ranges between a few and several hundred fold [18,26,31,37^39]. For instance, in rats, mice and rabbits, the level of liver AGP mRNA and plasma AGP protein increase 10- to 200-fold within 24 h of experimentally induced in£ammation. These increases are primarily attributed to changes in AGP gene transcription [40,41], although some evidence for additional posttranscriptional modulation has been reported [42]. IL-1, IL-6 and glucocorticoids are the major modulators of AGP gene expression in liver cells from human, rat, mouse, and rabbit [43^46]. In most instances, a strong synergistic action is achieved by the combination of the three factors [47^49]. It has been recently shown that another cytokine, interleukin-8, can also increase AGP production from isolated human hepatocytes [50]. In addition to cytokines and glucocorticoids, retinoic acids (RA) have also been

reported to play a role in the production of acute phase proteins. Concerning AGP expression, RA enhances the IL-6 response, but acts as a negative modulator of glucocorticoid-induced AGP mRNA synthesis [51,52]. In vivo AGP gene response to dexamethasone and cytokines has been reproduced in vitro using rat, mouse and human hepatoma cell lines as well as hepatocytes primary cultures. Among these cells, rat liver cells are exceptional in that glucocorticoids, such as dexamethasone, strongly stimulate AGP production in the absence of cytokines [49,53]. Thus, the regulation of rat AGP gene expression in hepatic cells provided a good model for studying the molecular mechanisms of the action of glucocorticoids on gene expression. In parallel, the AGP gene of various species has been isolated and sequenced (see above), this permitting the study of the transcriptional regulation of the AGP gene. Inserting AGP gene promoter sequences into reporter gene constructs allowed to determine cis-acting DNA sequences and trans-acting proteins involved in the acute phase response (Fig. 2). In rat AGP, IL-1 and IL-6 activities mediated by DNA sequences placed far upstream in the 5P-£ank-

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ing region (35 kb) termed the distal regulatory element (DRE) [54,55]. The DRE was dissected into a 5P 62-bp portion that mediates induction by IL-1 or phorbol ester, and a 3P 54-bp portion that mediates the IL-6 response. These two elements interact positively. The AGP DRE includes binding sites for transcriptional factors of the C/EBP family. Since cytokines strongly stimulate the expression of the C/EBPL in liver [56] and H-35 hepatoma cells, this C/EBP isoform is proposed to be an indirect mediator of the cytokine signal to the AGP gene [57]. Glucocorticoids act through a glucocorticoid responsive element that is in close proximity to the starting site of transcription, centred around 3110, within the so-called `minimal steroid responsive unit' (SRU) of the AGP promoter (3155 to 365) [41,58^ 60]. The SRU, like the DRE contains several binding sites for C/EBP transcription factors; two of these binding sites overlap with the glucocorticoid responsive element (GRE) and a strong positive co-operation between the GR and C/EBPL (CCAAT/enhancer binding protein L) was reported for the hormone induction of the AGP gene. Recently, it has been shown that one of the functions of the GR to activate AGP gene transcription is to recruit C/EBPL and to maintain it bound at its target DNA sequence (SRU) [61]. In addition, Chang et al. [62] identi¢ed a novel transcriptional intermediary factor, TIF1L, which could enhance the transcription of the AGP gene by the glucocorticoid receptor (GR) and C/EBPL. Using transgenic mice containing rat AGP gene constructs, Dewey et al. [63] provided evidence that the GRE and the DRE function in vivo. AGP gene regulation in other species is more closely related to rat than human. Although AGP gene regulation is remarkably similar among species, the enhancer sequence and its location are quite variable. Mice di¡er from rats, in that they possess more than one AGP gene; the level of mRNA for AGP-1 is higher than that for AGP-2. Both genes are induced dramatically following induction by agents such as LPS, turpentine, cytokines, glucocorticoids, and heavy metals [26,64,65]. The promoter region of the mouse AGP-1 gene contains a region termed the acute phase response element (APRE). This region was shown to mediate the induction of AGP expression in response to LPS [45^47]. The APRE contains a consensus C/EBP binding site that overlaps with a

GRE at its upstream side. Although this region showed a high degree of homology with the proximal GRE of the rat gene, it did not function as a glucocorticoid enhancer. In fact, mouse AGP gene induction is more complex and, involves both positive and negative transcription factors. The 180-bp region of the promoter contains four motifs recognised by a positive transcription factor, C/EBPL [66], and a negative cis element recognised by a negative factor (factor B) identi¢ed as nucleolin [67,68]. During the acute phase response, there is a dramatic increase in the level of C/EBPL, coupled to the decrease in factor B, resulting in the induction of AGP gene transcription. In addition to C/EBP and factor B, the transcription of the AGP gene is positively regulated by transcription factors YY1 [69] and Nopp140 [70]. Although YY1 activates the AGP promoter by relieving the negative action of the B element, Nopp140 functions as a transcriptional activator by interacting with C/EBPL to synergistically activate the AGP gene. In rabbit, regulation of the AGP gene is also controlled by the APRE consensus sequence during the in£ammatory reaction [31,71]. In vitro DNA binding studies have demonstrated that C/EBPL and C/EBPN are the major proteins responsible for the acute phase induction of AGP gene expression in the rabbit [72]. In addition to the in£ammatory mediators previously described, AGP gene expression can be modulated by a series of other molecules. AGP gene transcription appears to be regulated by both exogenous and endogenous factors. It has been shown that the repeated administration of phenobarbital (PB), a strong inducer of liver drug-metabolising enzymes [73] (mainly cytochromes P4502B1 and 2B2), also enhanced AGP serum levels in dogs and rats [74^ 76]. In PB-treated rats, AGP gene expression progressively increased within the 7-day administration period, reaching a maximum at day 9 [77]. These results were unexpected since AGP is not involved in steroid or drug metabolism. Nuclear run-on assays showed that in rat liver, the e¡ect of PB on AGP synthesis essentially occurred at the transcriptional level. In vitro studies showed that PB acted directly on hepatocytes by increasing AGP gene expression, and that an in£ammation-independent pathway mediated this e¡ect [49,78]. Transfection experiments using primary rat hepatocytes demonstrated that a

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17-bp sequence called PBRE (PB responsive element) and located within the SRU can confer PB inducibility to a heterologous gene [79]. This sequence is similar to that described in the bacillus Bacillus megaterium and rat CYP2B1/2 genes [80,81]. In vitro, this sequence binds liver nuclear factors with molecular weights of 43, 52, and 65 kDa in a PB-dependent manner; the 43-kDa factor is related to C/EBPK and the 52- and 65-kDa factors to the two subunits of NF-kB [82]. This new model of PB-induced AGP gene expression enabled the discovery of a new responsive element in the AGP promoter and helped prove the involvement of NF-kB within the SRU in addition to C/EBP factors. Finally, treatment of isolated rat hepatocytes with growth hormone (GH) in vitro inhibits AGP gene expression at the transcriptional level [83]. AGP gene expression remained inducible by IL-1, IL-6, and PB in GH-treated hepatocytes. Interestingly, liver AGP mRNA content was strongly increased in hypophysectomised rats and treatment of these animals with GH led to a decrease in mRNA expression. This negative regulation of AGP gene expression in vivo and in vitro strongly suggests that GH is a major endogenous regulator of constitutive AGP gene expression. The ¢nding that GH can regulate AGP gene expression raises the possibility that GH might regulate the expression of acute phase response genes in the liver during in£ammatory responses. This hypothesis is supported by the ¢nding that in GH-treated animals, serum AGP levels were not increased after thermal injury [84]. Moreover, transfection assays showed that the AGP promoter region that contains the PBRE (located at position 3147 to 3123) is involved in GHmediated AGP gene regulation. Furthermore, GH deeply modi¢es the pattern of nuclear protein binding to this region. This region does not contain a sequence that could be related to the already described growth hormone responsive element [85]. Thus AGP gene regulation by GH could be a good model to investigate novel DNA responsive elements and novel transacting factors. 4. AGP extra-hepatic expression and its regulation Extra-hepatic production of AGP and of other acute phase proteins has been described for the last

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40 years. However, the regulation of extra-hepatic AGP gene expression has only been examined recently, and the hypothesis that an acute phase response may take place in extra-hepatic cell types and may be regulated by in£ammatory mediators as observed in hepatocytes is now well admitted (Table 1). The ¢rst evidence of the presence of AGP as well as other serum glycoproteins in extra-hepatic tissues were probably done by investigators examining qualitative and quantitative alterations of normal serum glycoproteins in cancer [86^89]. In 1977, Twining and Brecher [90] identi¢ed, by immunological means, AGP, antithrombin III, and alpha;2-macroglobulin as components of the 90,000 g supernatant fraction of malignant and adjacent normal human breast, colon, and anal tissues, as well as malignant stomach and ileum whereas malignant lung tissue only contained AGP. If the association between cancer and AGP was clearly established, others reported that AGP was detectable in normal tissue such as human myocardium, using immunohistochemical techniques [91]. Gahmberg and Andersson [92] in 1978 described that speci¢c antibodies against human AGP reacted with human leukocytes such as lymphocytes, granulocytes and monocytes. The previously cited studies described the presence of AGP, but gave no direct proof of active synthesis of AGP in extra-hepatic tissue or cell types in normal or pathological conditions. Evidence was obtained for the active synthesis of AGP by human breast epithelial cells [93]. High levels of mRNA coding for AGP were detected in the placenta during early foetal development of the rat. This expression was con¢ned to the decidua in the uterus and was ¢rst observed approximately one day after implantation when proliferation of the decidua is already well advanced [94]. A team from Sweden [95] recently explored the possibility that endothelial cells produced AGP. Using primary cultures of human microvascular endothelial cells (HMVEC) from dermal tissue, they demonstrated that AGP mRNA and protein were constitutively expressed in endothelial cells. Studies provided evidence that cultured human granulocytes, the monoblastoid cell line THP-1 [96] and monocytes [96,97] synthesise and secrete AGP while neither T- nor B-lymphocytes do [96]. From these studies, it appears that certain acute

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phase reactants and especially AGP are produced by cell types (di¡erent from hepatocytes) from heterogeneous organs or tissues, including leukocytes. Although the exact role or function of AGP remains unknown or at least not totally understood, AGP can be considered as a natural anti-in£ammatory and immunomodulatory agent (see below). Consequently, one can raise the hypothesis that the local production of this acute phase protein at the site of the initial acute phase reaction may contribute to maintain homeostasis by reducing tissue damage associated with the in£ammatory process. Indeed, there is a growing body of evidence that the acute phase response may take place in extra-hepatic cell types, notably epithelial cells, and may be regulated by cytokines as observed in hepatocytes. Dube et al. [98] showed by an immunoperoxidase technique that

AGP was localised in prostatic epithelial cells from patients with prostatic in£ammatory disease. In order to provide new insights into the extra-hepatic and tissue-speci¢c expression of genes encoding the plasma proteins, Kalmovarin et al. [99] analysed the acute phase reaction in C57B1 mice after intra-peritoneal injections of bacterial lipopolysaccharide (LPS). AGP mRNA synthesis was induced only in kidney, but not in other extra-hepatic tissues examined, including thymus, adipose, spleen, testes, brain, heart and lung. Another study raises the possibility that enterocytes are involved in a local response to injury/in£ammation by producing many of the acute phase proteins under the control of cytokines (IL-1, IL-6, IFN and TNF) [100]. Boudreau et al. [101] provided evidence that glucocorticoids induced AGP gene expression in the rat intestinal epithelial

Table 1 Extra-hepatic expression of AGP Organs or cell types Kidney Adipose Spleen Thymus Heart Testes Ileum Stomach Colon Intestinal epithelial cells Prostatic epithelial cells Brain Breast Breast epithelial cells Uterus Decidua Lung Pulmonary ¢broblasts Pneumocyte II Alveolar macrophages Peritoneal macrophages Monocytes Lymphocytes Granulocytes Endothelial cells

Protein

+ [91] + [90] + [90] + [90] + [98] + [89,90] + [93] + [94] + [90] + [102] + [97] + + + + +

[96,97] [92,151] [92,151] [92,151] [95]

mRNA

Constitutive

Inducible

+ [99] 3 [99] 3 [99] 3 [99] 3 [99] 3 [99]

3 [99]

+ [99]

+ [101] 3 [99]

3 [99] + [102] + [97] + [102] + [97] 3 [97]

+ [95]

+ [91]

+ [90]

+ [90] + [93] 3 [94] 3 [90,102] 3 [102] +/3 [97] + + + + +

[96,97] [92,151] [92,151] [92,151] [95]

+ + + + +

[90] [90] [90] [101] [98]

+ [89,90]

+ + + + +

[94] [90,102] [97] [102] [97]

+ + + +

[96,97] [151] [151] [151]

The expression (+) or the absence of expression (3) of AGP protein and mRNA are described for the extra-hepatic tissues and cell types studied. When the AGP gene was expressed, constitutive (basal) or inducible (in£ammation, cancer) expression in the corresponding tissue or cell type is indicated.

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cell line IEC-6 and that TGFL antagonised this glucocorticoid-dependent induction. Data concerning the expression of AGP in the lung are controversial. Twining and Brecher found the protein in malignant lung tissue [90] while Kalmovarin did not detect AGP mRNA in the lung of mice treated with LPS [99]. Two recent studies con¢rmed that AGP gene expression was induced in lung tissue from human and rat during an in£ammatory process [97,102]. The hypothesis arising from these studies was that, in the absence of a systemic in£ammation, local expression of an immunomodulatory protein, such as AGP, might be particularly relevant in the alveolar space where the integrity of the structure is essential for the maintenance of lung function. AGP immunoreactivity was found in acutely in£amed or ¢brotic lungs, but not in normal lung tissue from rat or human. Interestingly, induction of local (intratracheal administration of LPS) as well as systemic (intraperitoneal injection of LPS, dexamethasone or turpentine) acute in£ammation in rats led to an increased AGP gene expression in the lung [102]. This suggests that the lung, like the liver, is involved in a local response to a local or distant injury by producing acute phase reactants under the control of in£ammatory mediators. The role of alveolar type II epithelial cell or pneumocyte II (PII) [102] and alveolar macrophages (AM) [97] in lung AGP expression was demonstrated in vivo and in vitro. Studies on rat AM and PII showed that unlike hepatocytes, constitutive AGP protein expression was barely detectable. However, after incubation with dexamethasone, both AGP mRNA expression and protein synthesis and secretion were up regulated, IL-1L potentiating the dexamethasone-induced e¡ect. Most of the newly synthesised protein, with a molecular weight corresponding to the mature glycoprotein, was found in the supernatant. These results are in agreement with others who have demonstrated that IL-1L modulates acute phase protein expression at both transcriptional and post-translational levels by increasing protein secretion [103]. As described in rat hepatocytes and hepatoma cell lines [44,104,105], AM [97] and PII [102] AGP gene expression in response to cytokines was strictly dependent on treatment with dexamethasone and IL-1L was found to be a more potent inducer of AGP expression than IL-6. The regulation of AGP gene ex-

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pression by glucocorticoids and acute phase mediators in AM and PII occurred, as described in hepatocytes, at both the transcriptional and posttranscriptional levels, and required the presence of protein factors [106]. The de novo synthesis of nuclear proteins belonging to the C/EBP family ^ especially the inducible isoforms of C/EBP (C/EBPL and C/EBPN) ^ was shown to be required for the induction of AGP gene expression under acute phase conditions [72,107]. Baumann et al. demonstrated that trans activation of C/EBP by glucocorticoids was necessary for AGP gene expression [56]. Thus, the involvement of C/EBP isoforms in the mediation of alveolar macrophage AGP gene up regulation is likely since it requires both new protein synthesis and the presence of glucocorticoids. This is in agreement with previous studies that suggested an important contribution of the C/EBPN isoform to glucocorticoid-induced AGP transcriptional activation in intestinal epithelial cells [101]. In addition to cytokines, another major in£ammatory product of macrophages, the lipid mediator PGE2 , also increased AGP mRNA levels in AM. It has been previously shown that in macrophages, PGE2 increased intracellular cAMP levels as well as protein kinase A activity [108] and that PGE2 was the arachidonic acid metabolite preferentially secreted by macrophages during in£ammation, whereas control cells mainly produced PGD2 [109]. Interestingly, PGD2 that does not increase PKA activity does not increase AGP gene expression (personal data). It is known that C/EBPL requires phosphorylation at several functional domains, such as nuclear translocation and DNA binding. Phosphorylation and trans-activation of a transcription factor belonging to the C/EBP family may mediate the cAMPinduced increase in AGP gene transcription. In this connection, Metz and Zi¡ showed that cAMP and the protein kinase A activator (forskolin) stimulate the C/EBP-related transcription factor NF-IL-6 to trans-locate to the nucleus and induce gene transcription of the cellular proto-oncogene c-fos [110]. The up regulation of AGP gene expression by PGE2 and cAMP has not been previously described in any cell types and further studies would provide new insights to better understand the mechanisms involved in this new activation pathway of AGP gene expression.

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5. Biological functions of AGP 5.1. Immunomodulatory properties AGP is considered as a natural anti-in£ammatory and immunomodulatory agent notably with respect to its anti-neutrophil and anti-complement activity [111]. Indeed, AGP has been shown to act in vitro and in vivo as an immunomodulating molecule. In vitro, AGP inhibits polymorphonuclear neutrophil activation [112], increases the secretion of an IL-1 inhibitor by murine macrophages, most probably the IL-1 receptor antagonist [113,114], and modulates LPS-induced cytokine secretion by monocytes^ macrophages [115]. More recently, it has been demonstrated using dynamic light-scattering particle sizing and particle mobility that AGP interacts directly with LPS [116]. In vitro studies using human monocytes showed that AGP-induced TNFK secretion is enhanced by serum binding proteins and depends on protein tyrosine kinase activation [117]. It has also been suggested that AGP is required to maintain capillary permeability [118] probably by increasing the polyanionic charge selectivity of the endothelial barrier [118,119]. Muchitsch et al. [120] suggested that the partially protective e¡ect of AGP in di¡erent rodent models of shock may be explained by enhancing the capillary barrier function and thereby maintaining the perfusion of vital organs. In vivo, AGP infusion was shown to protect galactosamine-sensitised or normal mice against hepatitis and lethal shock induced by TNFK [121]. It has been suggested that the potent platelet aggregationinhibitory activity of AGP [122] and its potent inhibition of neutrophil chemotaxis and oxidative metabolism [112] underlie its protective properties. More recently, AGP has been shown to speci¢cally inhibit TNFK-induced, but not anti-Fas-induced apoptosis of hepatocytes in mice. However, the authors concluded that AGP confer in vivo protection by an indirect mechanism since in vitro, AGP failed to protect the human hepatoma cells from TNFK+actinomycin D-induced apoptosis [123]. Previously characterised rat-AGP-transgenic mice [63], constitutively overexpressing AGP, were tested for their response to a combined challenge with TNF and galactosamine. Unexpectedly, transgenic mice were not pro-

tected by the endogenously overproduced AGP, although puri¢ed AGP from the serum of transgenic mice was as protective as the AGP from non-transgenic mice or rats. The authors concluded that AGP is protective only when its concentration is rapidly induced (i.e. by acute phase mediators), perhaps because of a constitutive production of an AGP-binding factor or inhibitor [124]. The immunomodulatory activity of AGP has been shown to depend on its glycosylation. For example, the inhibition of lymphocyte proliferation depends on the degree of branching of the glycans, ConA non-reactive human AGP variants being more e¡ective [125]. Aggregation inhibition of platelets is enhanced when AGP is desialylated [122]. Williams et al. [111] suggested that the sialyl Lewis X form of AGP, which is induced during in£ammation [126], ameliorates both complement and neutrophil-mediated injuries while a non-sialyl Lewis X form does not. Sialyl Lewis X is the ligand for the cell adhesion molecules E-selectin and P-selectin involved in the in£ammation-dependent adhesion of neutrophils, monocytes, or resting T-cells to endothelial cells or platelets [127]. It was shown using surface plasmon resonance spectroscopy that AGP from individuals with acute in£ammation expressing a high degree of sialyl Lewis X serve as a speci¢c ligand for an E-selectin-IgG chimeric molecule [128]. It was observed that sialylated oligosaccharides protected against immune complex-induced lung injury in the rat in vivo [129]. Thus, the in£ammation-induced increase in sialyl-Lewis X-substituted glycans on AGP might represent a mechanism for feedback inhibition of granulocyte extravasation into in£amed tissues (Fig. 3). In 1995, Rabehi et al. [130] suggested that AGP might prevent binding of soluble or virusbound envelope glycoprotein to CD4+ monocytic cells by binding human immunode¢ciency virus type 1 (HIV-1) Env glycoprotein via N-linked glycans. Together, these data show that AGP carbohydrate chains play a crucial role in the immunomodulating activities of the glycoprotein. Pukhalsky et al. [131] provided evidence that pseudo-AGP, consisting of carbohydrate chains attached to a protein free polymer, suppressed PHA- or anti-CD3 antibody induced lymphocyte proliferation in a dose-dependent manner. Pseudo-AGP also stimulated the LPS-induced

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Fig. 3. Hypothesis for the inhibition of leukocyte extravasation by AGP. Events leading to transmigration of leukocytes to a site of in£ammation are summarised. AGP expressing sialyl Lewisx interacts with E-selectin expressed at the surface of endothelial cells and compete with leukocytes expressing ESL-1, the ligand of E-selectin. Consequently, rolling, adhesion and extravasation of leukocytes may then be inhibited. From E.C. Havenaar, Thesis, Vrije Universiteit, Amsterdam, the Netherlands.

proin£ammatory cytokine production by mononuclear cells. 5.2. Drug binding to AGP (see [132] for review) Human serum albumin, lipoprotein and AGP are the most important drug binding proteins in plasma that can have important pharmacokinetic implications. Variations in AGP plasma levels occurring during in£ammatory processes can considerably alter the free plasma level of the drug without a¡ecting its total plasma concentration. Thus, the free concentration of the drug in plasma will more accurately re£ect the intensity of the pharmacological e¡ect. Due to its physical^chemical properties, AGP mainly binds basic and neutral drugs from endoge-

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nous as well as exogenous origins. AGP has the ability to bind basic drugs like tamoxifen [9] and propanolol [133]. It also binds vanilloids [134], IgG3, heparin, serotonin [9], platelet activating factor (PAF) [135], melatonin [136] and histamine [137]. Interestingly, AGP binds and carries molecules that modulate its gene expression (see regulation of hepatic AGP gene expression above): phorbol esters [134], but also acidic drugs, such as phenobarbital [138], retinoic acid [139] and endogenous steroids (cortisol) [140]. AGP as a drug carrier for steroids has been demonstrated since the end of the sixties [141]. More recently, AGP was found to also bind synthetic steroids (RU486) [140]. Discrepancies between bindingparameters were often described depending on the models and methods used to calculate the number of binding sites and the binding constant. For instance, one can conclude from the results of drug displacement studies that there is only one common binding site on AGP for all the basic drugs studied, while with other methods, such as the curvilinear Scatchard plots, more than one class of binding site is currently obtained. Up to seven binding sites have been described for estradiol ^ depending on the isolation method used [142] ^ while in vitro studies provided evidence that two classes of binding sites for basic and neutral drugs are present on AGP. It is generally assumed that in plasma, acidic drugs are mainly bound to human serum albumin. However, binding to AGP will contribute signi¢cantly to the total plasma binding of these drugs, especially in diseases in which the concentration of AGP increases and/or of human serum albumin decreases [138,143]. From the literature, it appeared that there is only one binding site on AGP for acidic drugs [144] excepted for phenobarbital for which two sites have been described [138]. The nature of drug binding to AGP has been the subject of several studies and has mainly pointed to hydrophobic bindings due to hydrophobic residues near the AGP binding site. However, the binding capacity of AGP depends upon the conformational change of the protein, the polarity of the ligand (interaction is weakest for the steroid with the highest polarity), the temperature, and several other amino acid residues lying at the periphery of the hydropho-

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bic domains of AGP. Although the binding of drugs to AGP has been shown to be mostly hydrophobic in nature, several data also point to an electrostatic interaction and a lot of studies have reported that in plasma, drug bindings are stereoselective, especially in the case of basic drugs. Among factors in£uencing the characteristics of drug bindings to AGP, pH is one of the important parameters, i.e. drug binding in plasma increases with increasing pH [145]. Desialylation can also a¡ect binding [146]; it reduced the propanolol binding, whereas the progesterone binding did not change. AGP is an acute phase protein, whose plasma levels can be used as a diagnostic and prognostic, and during clinical therapy. The large variations observed in the binding ratios of basic drugs in plasma during several physiological and pathological states are correlated with the large variations in the plasma level of AGP. This has implications for the monitoring of the free fractions of basic drugs during clinical therapy. The consequences of elevated serum AGP levels, often seen in several disease states, on the pharmacokinetic of drugs have been investigated using transgenic animals. Holladay et al. studied steady-state kinetics of imipramine [147] and pharmacokinetics and antidepressant activity of £uoxetine [148] in transgenic mice expressing serum AGP levels about 9-fold elevated over normal [63]. In conclusion, given the important number of the forementioned biological activities of AGP, there are numerous arguments suggesting that this constitutively produced glycoprotein plays a crucial role in maintaining homeostasis. Moreover, AGP gene expression is modulated quantitatively (protein levels) as well as qualitatively (microheterogeneity of the glycan chains) in various physiological and pathological disorders. Although extrahepatic expression has been described, the hepatic expression remains the most abundant. Studies in transgenic mice by Dente et al. [149] and by Dewey et al. [63] showed that both cis-acting regulatory elements and cellular environment (di¡usible factors, cell^cell interactionsT) are responsible for the liver speci¢city of AGP gene expression. Finally, AGP gene expression appears to be highly conserved since it is expressed in all the species studied including Euglena gracilis, an ancestral eucaryote unicellular alga [150].

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