Regulation of intercellular adhesion molecule-1 (CD54) gene ...

Regulation of intercellular adhesion molecule-1 (CD54) gene expression Kenneth A. Roebuck and Alison Finnegan Departments of Immunology/Microbiology and Rheumatology, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois

Abstract: Intercellular adhesion molecule-1 (ICAM-1, CD54) is an inducible cell adhesion glycoprotein of the immunoglobulin supergene family expressed on the surface of a wide variety of cell types. ICAM-1 interactions with the ␤2 integrins CD11a/CD18 (LFA-1) and CD11b/CD18 (MAC-1) on the surface of leukocytes are important for their transendothelial migration to sites of inflammation and their function as costimulatory molecules for T cell activation. ICAM-1 is constitutively expressed on the cell surface and is up-regulated in response to a variety of inflammatory mediators, including proinflammatory cytokines, hormones, cellular stresses, and virus infection. These stimuli increase ICAM-1 expression primarily through activation of ICAM-1 gene transcription. During the past decade much has been learned about the cell type- and stimulus-specific transcription of ICAM-1. The architecture of the ICAM-1 promoter is complex, containing a large number of binding sites for inducible transcription factors, the most important of which is nuclear factor-kappa B (NF-␬B). NF-␬B acts in concert with other transcription factors and co-activators via specific protein-protein interactions, which facilitate the assembly of distinct stereospecific transcription complexes on the ICAM-1 promoter. These transcription complexes presumably mediate the induction of ICAM-1 expression in different cell types and in response to different stimuli. In this review, we summarize our current understanding of ICAM-1 gene regulation with a particular emphasis on the transcription factors and signal transduction pathways critical for the cell type- and stimulus-specific activation of ICAM-1 gene transcription. J. Leukoc. Biol. 66: 876–888; 1999. Key Words: transcription · cytokines · promoter · transcription factors

of the immunoglobulin supergene family and contains five extracellular immunoglobulin-like domains that function in cell-cell and cell-matrix adhesive interactions [reviewed in ref. 1]. In contrast to other cell adhesion molecules, ICAM-1 is expressed in both hematopoietic and non-hematopoietic cells and mediates adhesive interactions by binding to two integrins belonging to the ␤2 subfamily i.e., CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1). ICAM-1 adhesive interactions are critical for the transendothelial migration of leukocytes and the activation of T cells where ICAM-1 binding functions as a co-activation signal [2]. ICAM-1 is also associated with a variety of inflammatory diseases and conditions including asthma, atherosclerosis, inflammatory bowl disease, acute respiratory distress syndrome, ischemia reperfusion injury, and autoimmune disease [3–10]. ICAM-1 is present constitutively on the cell surface of a wide variety of cell types including fibroblasts, leukocytes, keratinocytes, endothelial cells, and epithelial cells, and is upregulated in response to a number of inflammatory mediators, including retinoic acid, virus infection, oxidant stresses such as H2O2, and the proinflammatory cytokines, interleukin-1␤ (IL1␤), tumor necrosis factor ␣ (TNF-␣), and interferon-␥ (IFN-␥; Table 1) [1, 11–13]. In addition, many of these agonists can functionally cooperate to synergistically activate ICAM-1 transcription. For example, TNF-␣ and IFN-␥ together increase ICAM-1 expression greater than either cytokine alone [14]. The stimulatory effects of these mediators can be tempered by the anti-inflammatory cytokines transforming growth factor ␤ (TGF␤), IL-4, and IL-10, and the steroid hormone glucocorticoid, which in effect interfere with the signal transduction pathways and transcription factors critical for the induction of ICAM-1 expression [15–19]. The level of ICAM-1 expression on the surface of any given cell type depends on the concentrations of pro- and antiinflammatory mediators and on the availability of specific receptor-mediated signal transduction pathways and their nuclear transcription factor targets on the ICAM-1 promoter [20]. The major intracellular signal transduction pathways involved in the regulation of ICAM-1 expression include protein kinase C (PKC), the mitogen-activated protein (MAP) kinases (ERK, JNK, and p38), and the NF-␬B signaling

INTRODUCTION Intercellular adhesion molecule-1 (ICAM-1, CD54), a transmembrane glycoprotein of 505 amino acids, has a molecular mass ranging from 80 to 114 kDa depending on the degree of glycosylation, which varies with cell type. ICAM-1 is a member 876

Journal of Leukocyte Biology Volume 66, December 1999

Correspondence: Kenneth A. Roebuck, Department of Immunology/ Microbiology, Rush-Presbyterian-St. Luke’s Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612. E-mail:[email protected] Received August 12, 1999; accepted August 12, 1999.

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TABLE 1.

Cell Type-Specific Induction of ICAM-1 Expression

Cell type

Endothelial cell

Epithelial cell Fibroblast Keratinocyte Hepatocyte Leukocyte Smooth muscle cell

Stimuli

TNF-␣, IL-1, IL-6, thrombin, X-ray, PDTC, IFN-␥, endothelin-1, substance P, estradiol, shear stress, UV, TPA, LPS, measles virus oxidized LDL, H2O2, metal ions TNF-␣, IL-1, LPS, TPA, histamine, EBV, CMV, RSV, parainfluenza virus, rhinovirus TNF-␣, IL-1, IL-4, IFN-␥, retinoic acid, mycoplasma, PGE2 TNF-␣, histamine TNF-␣, IL-1, IFN-␥, IL-6 TNF-␣, IL-1, IFN-␥, IL-3, GM-CSF, TPA TNF-␣, PDGF

Abbreviations: TNF-␣, tumor necrosis factor ␣; IL, interleukin; IFN-␥, interferon-␥; GM-CSF, granulocyte-monocyte colony-stimulating factor; LPS, lipopolysaccharide; PMA, phorbol 12-myristate-13-acetate; RSV, respiratory syncytial virus; CMV, cytomegalovirus; UV, ultraviolet light A; LDL, lowdensity lipoprotein; PDGF, platelet-derived growth factor; EBV, Epstein-Barr virus; PGE, prostaglandin E; PDTC, pyrrolidine dithiocarbamate.

pathway [13, 21–26]. Nuclear transcription factors important for the activation of ICAM-1 expression include AP-1, NF-␬B, C/EBP, Ets, STAT, and Sp1 [1]. The abundant signaling pathways and transcription factors involved in ICAM-1 transcription reflect the complex cell type-specific and stimulus-specific regulation of the ICAM-1 gene.

proximal transcriptional initiation site [30]. However, only several hundred base pairs of 5’-flanking DNA appear to be required for the induction of the ICAM-1 gene by the proinflammatory cytokines TNF-␣, IL-1␤, and IFN-␥ (Fig. 2) [20, 43]. The induction of ICAM-1 transcription occurs rapidly, being detected by nuclear run-on analysis as early as 30 min after treatment [35]. This rapid induction of message indicates that ICAM-1 is an early response gene that utilizes latent transcription factors for the activation of its promoter. Indeed, the ICAM-1 promoter contains binding sites for a number of inducible sequence-specific transcription factors (Figs. 1 and 2). These elements appear to be important for both human and mouse ICAM-1 expression because they are evolutionarily conserved in both sequence and position within the two promoters [1, 44].

NF-␬B REGULATION OF ICAM-1 TRANSCRIPTION Although a number of cis-elements in the distal and proximal promoter regions contribute to ICAM-1 gene regulation, the proximal NF-␬B binding site located about 200 bp upstream of the translation start site has been shown by numerous studies to be particularly important for the induction of ICAM-1 transcrip-

ICAM-1 PROMOTER STRUCTURE In the 15 years since the discovery of ICAM-1, much as been learned about the regulation of this important cell adhesion molecule [27, 28]. ICAM-1 was originally identified by a monoclonal antibody in 1986 as the binding partner of LFA-1 (CD11a/CD18) [29]. The molecular cloning and sequencing of the ICAM-1 gene at the turn of the decade permitted functional analysis of the ICAM-1 promoter, which demonstrated that ICAM-1 is up-regulated primarily at the level of gene transcription [30–34], although several posttranscriptional mechanisms have also been reported [35–40]. The human ICAM-1 gene is located on chromosome 19 and consists of seven exons and six introns with each of the five immunoglobulin-like domains encoded by a separate exon [31]. The ICAM-1 protein is synthesized from transcripts of approximately 3.3 to 3.5 kb in length. These transcripts are generated from three different transcriptional initiation sites located 319, 123, and 41 bp upstream of the translation start site (Fig. 1). Although the proximal start site is utilized the majority of the time, the others may be differentially utilized depending on the cell type and activating stimuli, suggesting complex regulation of the ICAM-1 promoter [31]. However, the significance of this regulation is unclear because all transcripts appear to generate the same form of the ICAM-1 protein, although different ICAM-1 isoforms that arise through differential splicing have been identified in mouse [41]. More than 4 kb of the 5’-flanking DNA of the human ICAM-1 gene has been cloned and sequenced [31, 32, 42]. Analysis of the chromatin structure of the ICAM-1 gene revealed a constitutive DNase I hypersensitive site 1.5 kb upstream of the

Fig. 1. Sequence of the ICAM-1 promoter. Shown are 1,385 base pairs (bp) of human ICAM-1 promoter sequence. The ICAM-1 promoter contains a number of transcription factor binding sites (boxed sequences), including NF-␬B, AP-1, AP-2, AP-3, Ets-1, C/EBP, Sp1. The RARE (retinoic acid response element) binds retinoic acid receptors (RAR). Three transcriptional initiation sites indicated by right angle arrows have been mapped 319, 123, and 40–41 bp upstream of the translation start site (indicated by right angle arrow above the ATG codon). Consensus TATA boxes have been identified upstream of the 319 and 40–41 sites and a TATA-like element is present upstream of the third site.

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Fig. 2. Structure and regulation of the ICAM-1 promoter. The ICAM-1 promoter contains multiple transcription initiation sites (the two major ones at ⫺41 and ⫺319 relative to translation start site are indicated by right angle arrows). Upstream of each initiation site is a consensus TATA element that binds the general transcription factor IID (TFIID). The ICAM-1 promoter contains a number of binding sites for inducible transcription factors (indicated by solid rectangles) that mediate various activation signals elicited at the cell surface. The TNF-␣ and IL-1␤ responses are mediated by cooperativity between the transcription factors C/EBP and NF-␬B. The IFN-␥ response is mediated by STAT binding to the IFN-␥ response element (IRE). The H2O2 response is mediated by the antioxidant response elements (ARE), which bind the transcription factors AP-1 and Ets.

tion [11, 45]. NF-␬B is a member of the Rel family of transcription factors and is composed of two groups of structurally related, interacting proteins that bind DNA recognition sites as dimers and whose activity is regulated by subcellular location [46]. NF-␬B/Rel family members of the first group include NF-␬B1 (p50) and NF-␬B2 (p52), which are synthesized as precursor proteins of 105 (p105) and 100 (p100) kDa, respectively. The second group includes Rel A (p65), Rel B, and c-Rel, which are synthesized as mature proteins containing one or more potent activation domains. In resting cells, latent NF-␬B is complexed to a class of cytoplasmic retention proteins called inhibitors of NF-␬B (I-␬B). Signals that induce NF-␬B activity result in the phosphorylation of I-␬B on specific serine residues, marking the protein inhibitor for ubiquitination and subsequent proteolytic degradation by the ATP-dependent 26S proteasome complex [47]. The released NF-␬B is then free to move to the nucleus, bind to its recognition site, and activate gene transcription. Proteosome inhibitors known to block NF-␬B activity have been shown to inhibit the TNF-␣ induction of ICAM-1 expression in endothelial cells [48]. The p50 and p52 subunits of NF-␬B are derived from precursor proteins through the proteolytic degradation of an inhibitory carboxy-terminal domain containing seven ankyrin repeats, a domain also present in I-␬B proteins. p105 processing is induced by TNF-␣ and is mediated primarily by the lipid second messenger ceramide [49]. TNF-␣ increases intracellular ceramide through the activation of sphingomyelinases, which catalyze the breakdown of sphingomyelin to generate ceramide [50, 51] and induce ICAM-1 [3]. Inhibition of ceramide has been shown to block the induction of ICAM-1 expression [52]. The NF-␬B signaling pathway is activated by the proinflammatory cytokines TNF-␣ and IL-1␤, the major inducers of ICAM-1 expression in most cell types (Table 1). These cytokines activate NF-␬B through a kinase-mediated phosphorylation cascade involving a high molecular mass signaling complex called the signalsome (Fig. 3) [53]. Cytokine activation of the multiprotein signalsome results in the serine phosphorylation of I-␬B and the subsequent activation of NF-␬B [54]. Blockage of I-␬B phosphorylation by serine proteases or I-␬B degradation by inhibition of the 26S proteasome has been shown to suppress the TNF-␣ induction of ICAM-1 expression [25, 47]. Recently, an alternative activation pathway for NF-␬B independent of I-␬B degradation has been reported involving the tyrosine phosphorylation of I-␬B [55]. 878


Thus, NF-␬B appears to be activated through at least two distinct mechanisms involving the differential phosphorylation of I-␬B. The recent characterization of the ⬎600-kDa signalsome has identified a pair of Ser/Thr kinases important for I-␬B activation, namely the I-␬B kinase (IKK␣ and ␤) and the NF-␬Binducing kinase (NIK) [54, 56, 57]. IKK and NIK function in the signalsome as a complex with a scaffolding protein called

Fig. 3. TNF-␣, IL-1␤, and IFN-␥ signal transduction pathways activate ICAM-1 via NF-␬B and STAT binding to the ICAM-1 promoter. Shown are the major signal transduction pathways induced by cytokines to activate the ICAM-1 promoter. The IRE (IFN-␥ response element) binds either STAT-1 homodimers in response to IFN-␥ or STAT-1/3 heterodimers in response to IL-6. STAT-1 cooperates with the adjacent Sp1 binding site to mediate a full IFN-␥ response. The ␬B site binds Rel A homodimers or heterodimers composed of Rel A and cRel or NFKB1 (p50). TNF-␣ interaction with its receptor (TNF-R1) recruits TRAF-2, whereas IL-1␤ interaction with its receptor (IL-1R) recruits TRAF6. Both TRAF proteins interact with and activate NIK, which in turn activates the IKK␣/␤ kinase. The IKK␣/␤ heterodimer phosphorylates I-␬B, which marks it for degradation by the 26S proteasome permitting NF-␬B to translocate into the nucleus and bind the ICAM-1 promoter. IFN-␥ interacts with its receptor (IFN-R), which phosphorylates the associated JAK kinases. Activation of JAK-1 and JAK-2 phosphorylates STAT, permiting its dimerization and translocation to the nucleus.


IKAP that is critical for kinase activity [56, 58]. Phosphorylation of I-␬B requires the sequential phosphorylation of NIK and IKK within the signalsome (Fig. 3). Thus, NIK activates I-␬B through its phosphorylation of the IKK␣/IKK␤ heterodimer. Recent data utilizing IKK knockout mice indicate that IKK␤ is the dominant subunit in the transmission of inflammatory signals in vivo [59]. A model for the integration of the TNF-␣ and IL-1␤ signaling pathways suggest that ligand binding to the TNF-␣ and IL-1 receptors results in a number of TNF receptor-associated factors (TRAF), which associate with and transmit signals from the TNF-␣ and IL-1 receptors [60, 61]. Specifically, TRAF2 is recruited to the TNF-␣ receptor, whereas TRAF6 is recruited to the IL-1 receptor (Fig. 3). Because both TRAF proteins interact with the signalsome and phosphorylate NIK, the two pathways converge and go on to activate NF-␬B through the serine phosphorylation of I-␬B. The importance of the signalsome complex in the activation of ICAM-1 has recently been demonstrated in cultured synoviocytes using dominant negative mutants of IKK␤ to block TNF-␣ induction of ICAM-1 expression [Gary S. Firestein, University of California, San Diego, personal communication]. The NF-␬B element within the proximal ICAM-1 promoter is a variant NF-␬B binding site, and in contrast to consensus NF-␬B sites, sequences flanking it are critical for its function in ICAM-1 transcription [62]. The proximal NF-␬B site mediates a wide range of transcriptional responses that include the TNF-␣, IL-1␤, lipopolysaccharide (LPS), and thrombin responses [6, 13, 63, 64]. NF-␬B may also play a key role in the cell type- and stimulus-specific regulation of ICAM-1 because the proximal NF-␬B binding site can bind multiple forms of NF-␬B [65–68]. These different NF-␬B complexes can interact differentially with other transcription factors binding to the ICAM-1 promoter such as AP-1 and C/EBP [66, 69]. NF-␬B has also been shown to recruit co-activator proteins such as CREB binding protein (CBP), which functions as a nuclear integrator by coordinating diverse signaling events [70, 71]. Immediately upstream of and adjacent to the variant NF-␬B site is a CAAT/enhancer binding protein (C/EBP) site that functions in concert with the NF-␬B site to form a composite cytokine response element (Fig. 3). C/EBP, a family of bZip transcription factors that include C/EBP␣, C/EBP␤ (also known as NF-IL-6), and C/EBP␦, is activated by phosphorylation of a specific Thr residue via the MAP kinase signal transduction pathway [72]. The C/EBP site binds C/EBP␦ homodimers or C/EBP␤/␦ heterodimers, cooperates with the adjacent NF-␬B site to mediate the TNF-␣ and IL-1␤ induction of ICAM-1 [65, 73]. Specifically, Rel A and C/EBP␤ were shown to functionally cooperate to activate the TNF-␣ induction of ICAM-1 expression [43, 66]. Rel A contains a strong transactivation domain that is activated by phosphorylation of Ser529 by casein kinase II and Ser276 by protein kinase A [74, 75]. The NF-␬B site binds predominantly Rel A homodimers, which have been proposed to be the dominant form of NF-␬B involved in ICAM-1 transcription in vivo [67]. Nevertheless, the proximal site can also bind several NF-␬B heterodimers depending on the cell type [68]. For example, TNF-␣ induces Rel A/NF-␬B1 heterodimers in HepG2 and endothelial cells [43, 76], and Rel A/c-Rel heterodimers in Mel Juso cells [77].

The heterodimers also appear to be important for the cooperation with STAT proteins in the synergistic activation of ICAM-1 transcription by TNF-␣ and IFN-␥ [77–79]. The variant NF-␬B site also mediates the inhibitory effects of the steroid hormone glucocorticoid [80]. Glucocorticoids such as dexamethasone inhibit the TNF-␣ and phorbol ester induction of ICAM-1 expression by effecting NF-␬B binding to the ICAM-1 promoter [81, 82]. The glucocorticoid receptor (GR) down-regulates NF-␬B and ICAM-1 transcription in two ways [83]: first, through an increase in the transcription of the I-␬B gene; and second, through a physical interaction with the Rel A subunit [84]. Recently, a third mechanism has been shown to involve the competition of Rel A and GR for common coactivator proteins [85]. Each of these mechanisms interferes with the binding of NF-␬B to the ICAM-1 promoter, which in turn down-regulates gene transcription.

THE JAK/STAT PATHWAY AND IFN-␥ REGULATION OF ICAM-1 Another proinflammatory cytokine that is a potent activator of ICAM-1 expression in many cell types is the Type II interferon commonly known as IFN-␥ [86]. ICAM-1 is induced by IFN-␥ primarily through the IFN-␥ responsive element (IRE) located about 100 bp upstream of the translation start site [43, 87–89], although IFN-␥ has been reported to also stabilize ICAM-1 message [39, 40]. It has been shown that IFN-␥ induction of ICAM-1 transcription occurs through the activation of the Janus kinases (JAK)-signal transducers and activators of transcription (STAT) signal transduction pathway [18, 90] and Tyr and Ser phosphorylation of STAT-1 is critical for IFN-␥ activation of the ICAM-1 promoter [88]. JAKs are a family of protein tyrosine kinases that associate with the cytoplasmic tail of cytokine receptors [91]. Specifically, JAK1 and JAK2 are associated with IFN-␥ activation [92]: JAK1 associates with the ␣ chain of the receptor and JAK2 associates with the ␤ chain [93, 94]. JAK1 and JAK2 are maintained in a catalytically inactive state in resting cells [95]. However, on ligand binding, the ␣ and ␤ chains of the receptor dimerize, permitting the associated kinases JAK1 and JAK2 to cross-phosphorylate each other, which permits the STAT transcription factors to interact with the receptor via an SH2 domain [96, 97]. The activated JAKs phosphorylate STAT on specific tyrosine residues [98, 99], which allow the factor to dissociate from the receptor, form STAT dimers, and translocate to the nucleus to bind IRE promoter sites [100–102]. STAT-mediated transcription also requires serine phosphorylation of the STAT transactivation domain, suggesting the JAK-STAT pathway is linked to the MAP kinase pathway [103]. Indeed, a specific inhibitor of p38 MAP kinase prevented serine phosphorylation of STAT-1 and STAT-3 [104]. The ICAM-1 IRE is a palindromic STAT binding site, and is homologous to IFN-␥ activating sequences (GAS). However, the IRE site in the ICAM-1 promoter forms distinct binding complexes [105] and requires cooperation with the adjacent Sp1 binding site for a full transcriptional response to IFN-␥ [90]. The importance of tyrosine phosphorylation in the IFN-␥ induction of ICAM-1 was recently demonstrated using pervanaRoebuck and Finnegan ICAM-1 gene regulation

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date, a potent phosphatase inhibitor, which was able to mimic all the IFN-␥ signaling events important for the induction of ICAM-1 expression [106]. The acute phase cytokine IL-6 also mediates ICAM-1 transcription through the JAK-STAT pathway via the IRE promoter site [89]. However, IFN-␥ and IL-6 induce different STAT binding complexes on the ICAM-1 promoter. IFN-␥ induces STAT-1, whereas IL-6 induces both STAT-1 and STAT-3, which can bind to the ICAM-1 promoter as STAT-1 homodimers or STAT-1/STAT-3 heterodimers [107, 108]. Recently, several additional STAT binding sites have been identified in the far upstream region of the ICAM-1 promoter that are required for a full transcriptional response to IFN-␥ [42]. IFN-␥ cooperates with TNF-␣ to synergistically induce ICAM-1 expression [79]. This transcriptional synergy requires both the NF-␬B and IRE sites and is mediated by Rel A heterodimers and STAT-1␣ homodimers [77–79]. However, STAT-1␣ and NF-␬B do not bind cooperatively to the ICAM-1 promoter [43, 77], suggesting the ICAM-1 transcriptional synergy is mediated through their independent interaction with components of the basal transcription complex [78]. Alternatively, IFN-␥ has recently been shown to increase the degradation of I-␬B, providing a mechanism by which IFN-␥ can increase NF-␬B activity [109]. Oxidants and retinoic acid, two stimuli that activate ICAM-1 expression, also activate the JAK-STAT pathway [110–112]. However, it is not clear as to what extent these stimuli act through the JAK-STAT pathway to activate ICAM-1, since the retinoic acid response is mediated primarily through the retinoic acid receptor (RAR) response element (RARE) [113] and oxidants work primarily through the NF-␬B and AP-1 pathways [114, 115]. In addition to cytokines that up-regulate ICAM-1 expression, there are cytokines that inhibit ICAM-1. The IFN-␥ response is inhibited via a transcriptional mechanism by the antiinflammatory cytokines IL-10 and IL-4 [18, 19]. This negative cytokine signaling may involve two new classes of inhibitor proteins: suppressors of cytokine signaling (SOCS) proteins, which bind to and inhibit the enzymatic activity of the JAK family of tyrosine kinases [16–119]; and protein inhibitors of activated STAT (PIAS), which block the DNA binding activity of STAT-3 [120]. In this regard, IL-10 was recently demonstrated to activate SOCS-3 and inhibit tyrosine phosphorylation of STAT [121]. It is important that these anti-inflammatory cytokines and inhibitory proteins provide the means by which inflammatory molecules like ICAM-1 can be down-regulated to dampen and eventually resolve the inflammatory response.

AP-1 AND MAP KINASE REGULATION OF ICAM-1 The ICAM-1 promoter contains several AP-1 binding sites that may be important for ICAM-1 expression [31, 32]. AP-1 is a basic leucine zipper (bZip) factor and is composed of dimers of the Jun (cJun, JunB, JunD) and Fos (cFos, FosB, Fra1, and Fra2) transcription factor families [122]. AP-1 activity is regulated at both the transcriptional and posttranscriptional levels and is a major target of MAP kinase signaling pathways 880


[123]. A wide variety of stimuli, which are important for the induction of ICAM-1 expression, activate members of the MAP kinase family (Fig. 4). In particular, TNF-␣ activates three MAP kinase pathways: the extracellular signal-regulated kinase (ERK), the c-Jun amino-terminal kinase (JNK), and the p38 kinase pathway [124]. Inhibitor studies have shown that the MAP kinase pathways are important for the induction of ICAM-1 expression in endothelial cells [22, 125]. MAP kinases are Ser/Thr protein kinases that are activated by dual phosphorylation of Thr and Tyr residues [126] and their upstream activators have been extensively reviewed [127, 128]. Briefly, two MAP kinase (MAPK) kinases (MKKs), MKK4 and MKK7, transmit signals to JNK (Fig. 4). MKK7 is specific for

Fig. 4. Role of AP-1 and MAP kinase pathways in the activation of ICAM-1. The ICAM-1 promoter contains several AP-1 binding sites (indicated by solid rectangles in the ICAM-1 promter). AP-1 is composed of either Jun homodimers or Fos/Jun heterodimers. The c-jun and c-fos genes are activated by the induction of transcription factors via the different mitogen-activated protein (MAP) kinases, ERK-1/2, JNK, and p38. Each of the MAP kinase pathways is activated through a distinct upstream kinase cascade. ERK-1/2 is activated via MEK-1/2 in response to growth factors, cytokines, and phorbol esters. The JNK pathway is activated via the MKK4/7 and p38 via the MKK3/6 in response to cytokines, oxidants, and other stresses. The JNK and p38 pathways activate via phosphorylation the transcription factors ATF-2, Elk-1, and c-Jun. These factors in turn bind to cis-elements (Jun1 and Jun2) within the c-jun gene promoter to increase c-jun gene expression. The ERK pathway activates via phosphorylation the Ets family transcription factor Elk-1, which is a component of the SRF/TCF (serum response factor/ternary complex factor) complex. This complex activates the c-fos promoter, which can also be activated by STAT binding to the SIE (Sis-inducible element) and CREB (CRE binding protein) binding to the CRE (cAMP-responsive element).


JNK, whereas MKK4 may activate both JNK and p38 MAP kinases [129]. Two other MAPK kinases, MKK3 and MKK6, are important for p38 MAP kinase activation induced by TNF-␣ and stress [130–132]. The upstream signals leading to TNF-␣ activation of JNK are mediated through a TRAF2-dependent pathway [133, 134]. The ERK-1 and ERK-2 kinases are activated by MEK1 and MEK2, which are activated via the Ras and Raf kinases [135]. The three MAP kinase pathways regulate AP-1 activity by both increasing the expression of Jun and Fos and by phosphorylation of newly synthesized AP-1 complexes [122, 136]. Three promoter elements, CRE, SRE, and SIE control the induction of c-fos gene expression [137]. The c-fos CRE (cAMP responsive element) is bound by phosphorylated CREB (CRE binding protein) whose activity is controlled by protein kinase A [138]. The SRE (serum response element) is bound by serum response factor (SRF) that recruits Elk-1 to form a ternary complex [139]. Elk-1 belongs to the Ets family of transcription factors and phosphorylation of Elk-1 by the ERK, JNK, and p38 MAP kinases increases ternary complex formation with SRF [140– 142]. The third element of the c-fos promoter SIE (c-Sisinducible element) is bound by a STAT complex, consisting of STAT-1 and STAT-3 [143, 144]. The activation of the c-jun promoter is mediated by two DNA binding elements, Jun1 and Jun2, which are constitutively occupied by heterodimers of c-Jun/ATF-2 [145, 146]. JNK and p38 MAP kinases phosphorylate c-Jun and ATF-2 on specific Ser residues that are required to activate transcription of the c-jun gene [147]. Newly synthesized AP-1 is also regulated by the MAP kinase signaling pathway [123]. JNK phosphorylates c-Jun, whereas ATF-2 is phosphorylated by both JNK and p38 MAP kinases [147]. PKC activators such as phorbol esters [e.g., phorbol myristate acetate (PMA)] as well as oxidants and antioxidants also regulate AP-1 binding and transactivation activity [148]. The antioxidant pyrrolidine dithiocarbamate (PDTC) induced ICAM-1 promoter activity through the AP-1 binding site located about 320 bp upstream of the gene, which binds both cFos and cJun [149]. Another study showed this AP-1 site also binds JunD and Fra2, and transmits phorbol ester responses to the ICAM-1 promoter [150].

REGULATION OF ICAM-1 BY OTHER TRANSCRIPTION FACTORS Two Ets-1 binding sites have recently been identified by DNase I footprinting in the ICAM-1 proximal promoter located immediately upstream of the IRE [151]. These sites bind Ets-2 and ERM, another member of the Ets family, and mediate activation of the ICAM-1 promoter. Ets is a family of nuclear phosphoproteins that are targets of the Ras-MAPK signaling pathway. Ets transcription factors function as critical signaling integrators by interacting with other transcription factors such as AP-1. For example, the Ets binding sites located in the ICAM-1 distal promoter functionally cooperate with AP-1 to form the H2O2 responsive element [114]. The ICAM-1 gene is induced by retinoic acid [12, 152–154] and the ICAM-1 promoter contains a retinoic acid responsive element (RARE) located in the proximal promoter [113, 155].

The RARE binds retinoic receptors alpha, beta, and gamma as well as the retinoid X receptor alpha (RARX␣) [156]. Retinoic acid cooperates with TNF-␣ to synergistically activate ICAM-1 expression [157] through a functional interaction between RARX␣ and NF-␬B binding sites [158]. This is another example of the central role that NF-␬B plays by virtue of its many cooperative protein-protein interactions in the stimulusspecific regulation of the ICAM-1 promoter. The ICAM-1 promoter also contains AP-2, AP-3, and Sp1 binding sites [31, 32]. The Sp1 binding site in the proximal promoter has been shown to be required for basal transcription of the ICAM-1 gene [43]. The AP-2 site has been shown to mediate phorbol ester responses as well as the UV irradiation response [159]. The AP-3 site overlaps a C/EBP site but it is unknown whether this composite element contributes to ICAM-1 expression.

PKC REGULATION OF ICAM-1 ICAM-1 expression is increased by PKC activators such as phorbol ester and phorbol dibutyrate [36, 160–163] and PKC activity in a variety of cell types is required for the induction of ICAM-1 by inflammatory mediators such as IL-1␤, TNF-␣, IFN-␥, nitric oxide, UVB, and LPS [13, 21, 82, 164–169]. Indeed, pharmacological agents that block PKC activity inhibit induced ICAM-1 transcription, although different PKC isoforms may be involved depending on the cell type and stimuli [161, 169–172]. Thus, it appears that the PKC pathway plays a major role in the transcriptional induction of the ICAM-1 gene. In addition, PKC activation can also increase ICAM-1 expression by increasing the stability of ICAM-1 mRNA [35, 39, 40]. Activation of the PKC pathway leads to the activation of a number of transcription factors including NF-␬B, AP-1, AP-2, Egr-1, and C/EBP [173, 174]. However, the PKC-mediated induction of ICAM-1 appears to be mediated primarily by the proximal NF-␬B binding site [175]. Recent data indicate that the atypical PKC isoforms ␨ and ␭/␶ are involved in TNF-␣ activation of NF-␬B by a mechanism that involves phosphorylation of I-␬B [168, 175–178]. With the discovery of the I-␬B kinases IKK␣ and IKK␤, the role of atypical PKC in TNF-␣ signaling has been clarified (Fig. 3). It was found that overexpression of PKC␨ increases IKK␤ activity but not that of IKK␣, despite the fact that PKC␨ binds to both kinases. In TNF-␣-stimulated cells, transfection of the dominant negative mutant of PKC␨ inhibits the activation of IKK␤ but not that of IKK␣ [179]. This study further showed that TNF-␣ and phorbol ester activates different isoforms of PKC: TNF-␣ activates PKC␨, whereas phorbol ester activates PKC␣. However, recombinant forms of both PKC isoforms were able to phosphorylate in vitro specific Ser residues on IKK␤, demonstrating that PKC activates the NF-␬B pathway at the level of IKK␤ activation and I-␬B degradation [179]. Dominant-negative mutants of PKC␨ were also able to inhibit the kinase activity of MEK and ERK, suggesting that IKK␤ is an upstream activator of the MAP kinase pathway [178]. These recent studies indicate a critical role for the PKC isoforms in the NF-␬B pathway. PKC isoform activation of the NF-␬B pathway may also require a redox-sensitive component because antioxidants inhibit the Roebuck and Finnegan ICAM-1 gene regulation

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PMA and TNF-␣ induction of NF-␬B and ICAM-1 expression [168, 180].

CELLULAR STRESS REGULATION OF ICAM-1 ICAM-1 expression is induced by a variety of extracellular stresses including those generated by oxidants, antioxidants, radiation, heavy metals, and shear forces [115, 149, 181–184]. Most of these stresses are mediated by the generation of reactive oxygen or nitrogen species (ROS and RNS, respectively) such as superoxide, nitric oxide, and hydrogen peroxide, which function as intracellular signaling molecules in the activation of ICAM-1 [114, 115, 167, 168, 180, 185–191]. These stress responses can be blocked by antioxidant inhibitors and are mediated primarily by NF-␬B binding to the ICAM-1 promoter [115, 189, 192, 193]. However, other transcription factors such as AP-1, Ets, STAT, and AP-2 have also been reported to be activated by ROS and mediate stress responses, suggesting these factors may also contribute to the stress regulation of ICAM-1 [110, 149, 159, 194]. ROS activation signals regulate ICAM-1 gene expression through multiple intracellular pathways. Roebuck et al. [114, 191] demonstrated that the reactive oxidant H2O2 induction of ICAM-1 in endothelial cells was distinct from that induced by TNF-␣. Recently, Rahman et al. [168] showed that TNF-␣ induced ICAM-1 through a redox mechanism involving the PKC activation of NF-␬B. These data suggest that H2O2 and TNF-␣ can activate distinct signaling pathways for the induction of ICAM-1 expression [195–197]. H2O2 activates tyrosine kinase activity, increasing the phosphorylation of the Src tyrosine kinase [Roebuck and Finnegan, unpublished results]. Src activation is the initial step in the activation of the MAP kinase pathway and the activation of the transcription factors AP-1 and NF-␬B [198]. In this regard, it has been shown that H2O2 can rapidly activate ERK and increase AP-1 and NF-␬B binding activity [194, 199–201]. It appears that exogenous H2O2 activates ICAM-1 transcription primarily through the MAP kinase pathway, whereas the redox mechanism of TNF-␣ induction of ICAM-1 involves the PKC pathway. The signaling and DNA binding studies are in close agreement with the functional analysis of the ICAM-1 promoter, demonstrating the involvement of different cis-elements in the H2O2 and TNF-␣ responses [114]. Elements in the distal region of the ICAM-1 promoter are required for the H2O2 response but were not essential for the TNF-␣ response [114]. In contrast, deletion of proximal promoter sequences in which the NF-␬B binding site was removed eliminated the TNF-␣ response. The H2O2 responsive region contains two 16-base-pair repeat binding sites for the transcription factors AP-1 and Ets [114]. Similar AP-1/Ets composite sites have been shown to mediate oxidant stress responses via cooperativity between AP-1 and Ets [202]. AP-1 and Ets can physically interact to form ternary complexes containing JunB, cJun, and Ets-2 that functionally cooperate to mediate H2O2 responses [203, 204]. Overexpression of JunB was shown to stimulate ICAM-1 promoter activity, demonstrating the involvement of AP-1 in ICAM-1 transcription [114]. The AP-1/Ets repeats are also similar to the so-called antioxidant response element (ARE) [205], a cis882


acting sequence element first identified in the oxi-protective enzyme genes for glutathione S-transferase Ya subunit and gamma-glutamylcysteine synthetase catalytic subunit [202, 206, 207]. The ARE has been shown to function independently of AP-1 binding and interact with distinct DNA binding proteins [207]. ICAM-1 expression is induced by both viral infections and invasive microorganisms [208–214]. Viruses can activate ICAM-1 through the direct effects of a viral gene product or through activation of cellular transcription factors. For example, the HBV X protein and the HTLV-1 Tax protein both directly transactivate the ICAM-1 promoter, the latter through the IRE site [211, 213]. In contrast, RSV and rhinovirus infection induce ICAM-1 transcription through the activation of NF-␬B [73, 208]. Invasive microorganisms appear to also induce ICAM-1 expression through NF-␬B [215].

CONCLUSIONS AND FUTURE PERSPECTIVES ICAM-1 gene transcription is regulated in a complex cell typeand stimulus-specific manner through the inducible transcription factor NF-␬B and its interactions with other transcription factors bound to the ICAM-1 promoter. These cooperative interactions with different NF-␬B complexes facilitate the assembly of distinct transcription complexes on the ICAM-1 promoter. It is the ratio and subunit composition of these transcription factors and their DNA-protein and protein-protein cooperative interactions on the ICAM-1 promoter that ultimately determine the particular expression pattern of ICAM-1 in a given cell type and in response to a particular stimulus. A complete understanding of the cell type- and stimulus-specific regulation of the ICAM-1 gene will require a more detailed analysis of the relationship between the architecture of the ICAM-1 promoter and the higher-order protein-protein interactions of the transcription factors the promoter directs in the assembly of an active transcription complex. This understanding will also entail a further analysis of the various signal transduction pathways that transmit extracellular signals to the nuclear transcription factors assembled on the ICAM-1 promoter. Given the importance of ICAM-1 as a major inflammatory molecule, continued molecular studies on the regulation of the ICAM-1 gene will be critical for the future development of effective anti-inflammatory strategies suitable for therapeutic intervention of such inflammatory conditions as ischemiareperfusion injury, acute respiratory distress syndrome, atherosclerosis, and inflammatory bowel disease.

ACKNOWLEDGMENTS This work was supported by grants from the American Heart Association (K.A.R. and A.F) and American Lung Association (K.A.R.) and by National Institutes of Health grants AR45835 (K. A. R.), AR45652, and AR45410 (A.F.).

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