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The Proceedings of the American Thoracic Society 1:239-246 (2004)
© 2004 The American Thoracic Society

Mechanisms of Glucocorticoid Receptor Action in Noninflammatory and Inflammatory Cells

Brian M. Necela and John A. Cidlowski

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

Correspondence and requests for reprints should be addressed to John A. Cidlowski, Ph.D., Laboratory of Signal Transduction, Building 101, MD F3-07, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709. E-mail: cidlowski{at}niehs.nih.gov

Glucocorticoids exert profound and diverse physiological effects on a wide range of cell types. Produced and released from the adrenal cortex in response to stress, levels of glucocorticoids are under the control of the hypothalamic–pituitary–adrenal axis. Glucocorticoids participate in numerous physiological processes such as glucose homeostasis; protein, lipid, and carbohydrate metabolism; development; neuorobiology; and programmed cell death. Glucocorticoids exert potent immunosuppressive and antiinflammatory actions in a cell type–specific manner largely through the interruption of cytokine-mediated pathways. These antiinflammatory actions are also complemented by the ability of glucocorticoids to induce apoptosis in many cells including thymocytes, blood monocytes, and peripheral T cells. As a class of drugs, glucocorticoids are among the most widely prescribed in the world for the treatment of immune and inflammatory diseases, including asthma, rheumatoid arthritis, ulcerative colitis, and allergic rhinitis. They are also a component of many chemotherapy regimens for the treatment of leukemias, lymphomas, and myelomas because of their role in the induction of apoptosis. However, long-term use of glucocorticoids has been limited by adverse side effects ranging from suppression of the hypothalamic–pituitary axis and growth retardation to osteoporosis, in addition to the development of glucocorticoid resistance. These undesired side effects of glucocorticoids are hypothesized to occur mainly through activation of gene transcription, whereas the beneficial antiinflammatory effects of glucocorticoids involve mainly mechanisms of gene repression. Understanding the molecular basis of glucocorticoid-induced side effects requires an understanding of their actions on homeostatic signaling processes in all cell types. In this review, we discuss the basic cellular and molecular signaling mechanisms of glucocorticoid action during noninflammatory and inflammatory situations.


   The Glucocorticoid Receptor
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The biological actions of glucocorticoids are mediated through the intracellular glucocorticoid receptor (GR), which belongs to the nuclear receptor subfamily that includes receptors for mineralocorticoids, estrogen and thyroid hormones, retinoic acid, and vitamin D (1). The glucocorticoid receptor is an evolutionarily conserved transcription factor found in such diverse species as Xenopus, trout, rat, and human. The human glucocorticoid receptor is the product of one gene located on the long arm of chromosome 5 (region 5q31p) (2). The gene consists of nine exons, with the protein-coding region in exons 2–9. Three promoters (1A, 1B, and 1C) have been identified for the human glucocorticoid receptor gene (3). The physiological relevance of the multiple promoters remains unclear but may provide a mechanism for tissue-specific expression and regulation.

Alternative splicing of pre-mRNA generates two different isoforms of human glucocorticoid receptor, hGR{alpha} and hGRß. The classic glucocorticoid receptor, hGR{alpha}, consists of 777 amino acids and is expressed in virtually all cell types. The hGRß isoform is generated by alternative splicing of the last exon, resulting in a protein of 742 amino acids that diverges at its C terminus. The final 15 amino acids of the C-terminal domain are unique to hGRß. In contrast to hGR{alpha}, the hGRß isoform localizes constitutively to the nucleus and is unable to bind steroids (4). In cell culture, overexpressed hGRß acts as a dominant negative on hGR{alpha}-mediated transactivation (5). Because of large differences in the levels of expression of hGRß and hGR{alpha}, the physiological relevance of hGRß has been controversial. However, hGRß has been identified as a contributing factor to glucocorticoid resistance in several pathological conditions (6–8). In addition, expression of hGRß appears to be enhanced by the proinflammatory cytokines tumor necrosis factor (TNF)-{alpha} and interleukin (IL)-1 (9). An additional form of hGR{alpha} (B isoform) has been identified as a product of alternative translation initiation (10). Translation from an alternative start site at codon 27 of the hGR gene produces the truncated B isoform. The generation of a B isoform of hGRß also exists (C. M. Jewell and J. A. Cidlowski, unpublished observations). The hGR{alpha}-B isoform appears to be expressed in the same cell types as hGR{alpha} and may activate gene transcription better in certain promoter contexts (10). The consequence of expression of the B isoforms of hGR{alpha} and hGRß on physiological processes remains elusive.

The glucocorticoid receptor protein possesses a modular structure containing three major domains (Figure 1): (1) a variable N-terminal transactivation domain, (2) a central DNA-binding domain, and (3) a C-terminal ligand-binding domain (11). The N-terminal domain contains the AF-1 transcriptional activation domain required for transcriptional enhancement and association with basal transcription factors (12, 13). The central DNA-binding domain is composed of two highly conserved zinc finger regions critical for dimerization, target site binding, transcriptional activation, and repression (13, 14). The C-terminal ligand-binding domain serves as the binding site for hormones, chaperone hsp90, and coactivators (13, 14) (Figure 1).



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  		Figure 1. A diagram of the molecular nature of the human glucocorticoid receptor.

 

   BASIC MECHANISMS OF GLUCOCORTICOID RECEPTOR ACTION IN NONINFLAMMATORY CELLS
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The glucocorticoid receptor participates in numerous physiological processes required for many facets of cell homeostasis. These physiological actions of glucocorticoids occur in diverse cell types that range from hepatocytes and epithelial cells to neurons. In these cell types, the glucocorticoid receptor regulates numerous genes that encode enzymes of carbohydrate and amino acid metabolism, hormones, hormone receptors, acute-phase proteins, enzymes of xenobiotic metabolism, components of antibacterial defense, and serum proteins. The glucocorticoid receptor regulates the expression of these genes by three basic modes of action (Figure 2): (1) binding to glucocorticoid response elements (GREs) in target genes to activate gene transcription, (2) inhibition of target gene transcription through direct DNA binding, and (3) gene regulation by physical interaction with other transcription factors. In this section, we discuss in detail the molecular mechanisms behind these modes of glucocorticoid receptor action that occur in cell types of noninflammatory origin.



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  		Figure 2. Basic mechanisms of glucocorticoid receptor (GR) action. Left: The GR resides in the cytoplasm complexed with several chaperones including hsp90 and immunophilin p59. On binding to glucocorticoids, the activated receptor dissociates from the attached accessory proteins and translocates into the nucleus. Middle: The GR then regulates the expression of genes by several basic modes of action. From top to bottom: The GR binds as a dimer to glucocorticoid response elements (GREs) in target genes to activate gene transcription; the GR binds to negative GREs (nGREs) and inhibits target gene transcription; the GR physically interacts with the c-Jun subunit of the AP-1 complex to inhibit AP-1-mediated gene expression; the GR physically interacts with the p65 (RelA) subunit of NF-{kappa}B and represses NF-{kappa}B-regulated gene expression; the GR physically interacts with members of the STAT family (STAT1, STAT5, and STAT3) and synergistically enhances STAT-regulated gene transcription. GTM = general transcriptional machinery; P = phosphate. Right: Examples of genes regulated by the GR by the various mechanisms are shown.

 
Activation and Translocation
In the absence of hormone, GR{alpha} resides in the cytoplasm as a multiprotein complex composed of chaperone proteins hsp90 and hsp70, immunophilin p59, and phosphoprotein p23 (14). Chaperone hsp90 maintains GR in a favorable conformational state required for high-affinity ligand binding and cytoplasmic retention. Binding of glucocorticoid agonists to the cytoplasmic GR induces the release of hsp90, resulting in a conformational change that unmasks the nuclear localization signal. The receptor then translocates to the nucleus, where it can act through several modes of action, as discussed below (Figure 2).

Activation of Gene Expression
In the nucleus, the activated hormone-bound GR dimerizes and binds in the major groove of the DNA through its central zinc finger DNA-binding domain. The DNA-binding domain recognizes distinct palindromic DNA sequences termed glucocorticoid response elements (GREs), usually located in the promoter of GR-regulated genes. The glucocorticoid response element, 5'-TGTACAnnnTCTTGT-3' (where n represents any nucleotide), differs among promoters of genes in copy number, sequence, and location with respect to each other and sites of other transcription factors. These factors and other cellular influences contribute to the extent to which an individual gene is activated or repressed. Binding of the GR to the response element in the promoter results in an allosterically induced conformational change within the receptor (15). The allosteric interaction promotes the recruitment of several coactivator complexes critical for remodeling of chromatin structure. The GR interacts with cAMP response element–binding protein (CREB)–binding protein/p300 and p/CAF, both of which contain intrinsic histone acetylase activity (16–18). These coactivators acetylate lysine residues in core histones to induce nucleosomal rearrangement and DNA unwinding. Other coactivator complexes such as steroid receptor coactivator-1, p/CIF, SWI/SNF, and GRIP1/TIF2/NcoA-1 contribute to the chromatin-remodeling process (16–18). Nucleosomal rearrangement leads to promoter accessibility and the recruitment of the basal transcriptional machinery, including TATA box-binding protein (TBP), TBP-associated factors, and RNA polymerase II. The concerted assembly of these factors results in the stimulation of selective gene transcription.

Repression of Gene Activation by DNA-dependent Mechanisms
In certain promoter contexts, binding of the glucocorticoid receptor to its response element leads to repression of gene activation. The GR can inhibit gene transcription through these "negative" GREs (nGREs) primarily by two mechanisms. First, the GR can compete for binding with an nGRE that overlaps with another transcription factor site. Binding of the GR to the nGRE prevents or displaces binding of the transcription factor, resulting in termination of transcription of that particular gene. Examples of genes regulated through this mechanism include the osteocalcin and prolactin genes (19, 20). The second mechanism of genomically mediated repression involves a composite GRE, in which the nGRE-bound GR interacts with transcription factors on adjacent binding sites. For example, in the proliferin gene promoter, a GRE and a binding site for the transcription factor activator protein-1 (AP-1) complex lie adjacent to each other (21). GR interacts with the AP-1 complex and, depending on the subunit composition of AP-1, either represses or enhances transcription. Repression by composite GREs has also been described for promoters of proopiomelanocortin and human corticotropin-releasing hormone (22, 23). In some cases, the mechanism by which the GR–nGRE interaction represses transcription in the context of the promoter remains largely undefined; however, it probably incorporates one of the former two modes of actions. Such nGREs have been identified in genes encoding Type 1 vasoactive intestinal polypeptide receptor, glutathione S-transferase, and insulin (24–26).

Regulation of Gene Activation by DNA-independent Mechanisms
The glucocorticoid receptor can also repress gene activation by mechanisms independent of direct binding to a glucocorticoid response element (27). This mechanism of action has been characterized for two transcription factors: AP-1 and nuclear factor {kappa}B (NF-{kappa}B). For example, the collagenase gene is repressed by glucocorticoids but contains no binding sites for the GR (28, 29). The glucocorticoid receptor physically interacts and represses the transcriptional activity of the AP-1 transcription factor complex required for regulation of the gene (28, 29). The GR/AP-1 interaction results in mutual antagonism as c-Jun, a component of AP-1, can reciprocally repress GR-mediated gene activation independent of its DNA-binding activity (29). Similar mutual antagonism also occurs between the glucocorticoid receptor and NF-{kappa}B. The most prevalent form of NF-{kappa}B is composed of two subunits, p50 and the transcriptionally active p65 (RelA) subunit. The glucocorticoid receptor represses NF-{kappa}B transcriptional activity, independent of DNA binding, by physically interacting with the p65 (RelA) subunit (30).

The glucocorticoid receptor also physically interacts with members of the signal transduction-activated transcription (STAT) factor family such as STAT3 and STAT5 (a and b). The outcome of this interaction depends largely on the promoter context, stimuli, and STAT protein involved. For example, the interaction of IL-6–activated STAT3 and the GR results in synergistic enhancement of the glucocorticoid-responsive mouse mammary tumor virus (MMTV) promoter and IL-6–regulated promoters from the rat {alpha}2-macroglobulin and {gamma}-fibrinogen genes (31–33). In contrast, GR interaction with IL-2–activated STAT5 leads to synergistic activation of the ß-casein promoter, but antagonism of the MMTV promoter (34). Given that AP-1, NF-{kappa}B, and STAT are key mediators of cytokine signaling and the inflammatory response, we discuss their interactions with glucocorticoid receptor in greater detail in the next section.


   MECHANISMS OF GLUCOCORTICOID RECEPTOR ACTION IN INFLAMMATORY CELLS
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The cellular and molecular events underlying inflammatory and autoimmune disorders are driven and perpetuated by numerous molecules with diverse roles such as cytokines, chemokines, growth factors, adhesion molecules, and inflammatory enzymes. These molecules mediate the inflammatory response in a variety of cell types that include macrophages, eosinophils, mast cells, T lymphocytes, dendritic cells, endothelial cells, epithelial cells, and neutrophils. Glucocorticoids exert widespread antiinflammatory actions in these cell types by interfering with the proinflammatory signaling process by both genomic and nongenomic mechanisms, often in a cell type–specific manner. Glucocorticoids can act by (1) increasing the expression of antiinflammatory proteins, (2) inhibiting MAP kinases required for proinflammatory gene activation, and (3) inducing programmed cell death in inflammatory cell types. However, these mechanisms alone cannot account for the widespread antiinflammatory actions of glucocorticoids. Rather, many of the antiinflammatory actions of glucocorticoids have been attributed to direct inhibition of the transcription factors AP-1 and NF-{kappa}B, central mediators of inflammatory gene expression. In this section, we highlight the basic mechanisms of glucocorticoid receptor signaling that contribute to the antiinflammatory actions of glucocorticoids in inflammatory cell types. In addition, we discuss how the homeostatic signaling of the GR within these cell types can be regulated by the same proinflammatory transcription factors it represses.

Regulation of Genes Encoding Antiinflammatory Molecules
In a few cell types, glucocorticoids increase the synthesis of several antiinflammatory proteins important for repression of inflammation. Although these proteins may partially contribute to the cell-specific antiinflammatory actions, their impact in the widespread actions of glucocorticoids is probably minimal. Antiinflammatory proteins upregulated by glucocorticoids include lipocortin-1, serum leukocyte protease inhibitor, IL-10, IL-1 receptor antagonist, and neutral endopeptidase (35). GR increases the expression of these proteins, presumably through DNA-dependent gene activation; however, the mechanisms responsible remain largely undefined.

Repression of Activator Protein-1 Signaling
AP-1 is a key mediator of cytokine signaling and is required for the activation of numerous proinflammatory genes (Figure 3) (36). The AP-1 complex is composed of a homo/heterodimer of the basic leucine zipper transcription factors Fos (c-Fos, FosB, Fra1, and Fra2) and Jun (c-Jun, JunB, and JunD). Only the Fos subunit contains transcriptional activity, and thus only dimer combinations containing a Fos family member can activate gene expression. The AP-1 complex composed of c-Fos/c-Jun dimer is the most prevalent combination within the cell. Proinflammatory cytokines such as TNF-{alpha} and IL-1ß activate the formation of the c-Fos/c-Jun heterodimer by stimulating the activation of the c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family (37). JNK phosphorylates the c-Jun subunit of AP-1, eliciting its dimerization with c-Fos. The heterodimer binds AP-1 response elements in promoters of numerous proinflammatory genes, attenuating the inflammatory response.



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  		Figure 3. Mechanisms of cross-talk between the glucocorticoid receptor and the AP-1 complex. Cytokines such as IL-1ß and TNF-{alpha} bind to and activate membrane-bound cytokine receptors. In turn, the cytokine receptor activates c-Jun N-terminal kinase (JNK), a member of the MAPK family. JNK phosphorylates the c-Jun subunit of AP-1, which is localized in the cytoplasm. Phosphorylation of c-Jun induces its activation and subsequent translocation into the nucleus. The c-Jun subunit then dimerizes with the transcriptionally active c-Fos subunit, and binds AP-1 response elements to regulate gene expression. The c-Jun subunit of AP-1 can also physically interact with the GR and repress GR-mediated gene transcription. Reciprocally, the GR can physi-cally interact with c-Jun and repress AP-1-mediated gene expression. The mechanism by which physical interaction between c-Jun and the GR leads to mutual antagonism remains unclear. Alternatively, the GR can repress AP-1 signaling through induction of the MAPK phosphatase-1 (MKP-1) gene. MKP-1 prevents phosphorylation of JNK and its subsequent activation.

 
The glucocorticoid receptor can repress AP-1 transcriptional activity by physically interacting with the c-Jun subunit (Figure 3) (29). Antagonism by the GR does not involve its direct binding to AP-1 response elements; however, the DNA-binding domain of the GR appears to be required for the effect. In turn, the c-Jun subunit can antagonize GR-mediated gene transactivation (Figure 3). The detailed mechanism behind the mutual antagonism remains incompletely understood; however, it does not appear to involve competition for limiting coactivators (38). An alternative mechanism by which the glucocorticoid receptor can repress AP-1 signaling is through induction of the MAPK phosphatase-1 (MKP-1) gene (39, 40). MKP-1 prevents phosphorylation and subsequent activation of JNK required for regulating c-Jun activity (Figure 3).

Repression of NF-{kappa}B Signaling
NF-{kappa}B is a ubiquitous transcription factor that plays a pivotal role in amplifying inflammatory and immune responses (41). NF-{kappa}B is a dimer protein composed of p50 and a transcriptionally active subunit, p65 (RelA). Both unactivated subunits of NF-{kappa}B are localized in the cytoplasm because of their association with inhibitory proteins (I-{kappa}B). Activation of NF-{kappa}B occurs in response to proinflammatory cytokines such as TNF-{alpha}, IL-1ß, IL-2, IL-17, and granulocyte-macrophage colony-stimulating factor. Essentially, binding of the cytokines to their appropriate receptors induces the activation of a kinase cascade leading to the phosphorylation of I-{kappa}B by inhibitory {kappa} kinase (Figure 4). Phosphorylation of I-{kappa}B by kinases leads to its subsequent proteolysis and release of the bound p65 and p50 subunits. The free NF-{kappa}B subunits translocate to the nucleus, dimerize, and bind NF-{kappa}B response elements in numerous proinflammatory genes as well as the I-{kappa}B{alpha} gene. NF-{kappa}B activates proinflammatory genes that encode the cytokines IL-1ß, TNF-{alpha}, and granulocyte-macrophage colony-stimulating factor; chemokines IL-8, macrophage inflammatory protein-1a, and monocyte chemoattractant protein 1; intercellular adhesion molecule-1; and the inflammatory enzyme inducible nitric oxide synthase. Production of the proinflammatory cytokines generates a positive feedback loop amplifying the inflammatory response. In contrast, activation of the I-{kappa}B{alpha} gene acts as a negative regulatory loop by increasing the production of I-{kappa}B{alpha} protein.



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  		Figure 4. Mechanisms of cross-talk between the glucocorticoid receptor and NF-{kappa}B. The NF-{kappa}B transcription factor is composed of two subunits, p50 and p65 (RelA). The subunits are sequestered in the cytoplasm through the interaction of the inhibitory protein I-{kappa}B. Binding of proinflammatory cytokines to their appropriate receptors induces the activation of a kinase cascade leading to the phosphorylation of I-{kappa}B by inhibitory {kappa} kinase (IKK). Phosphorylation of I-{kappa}B by IKK leads to the subsequent degradation of I-{kappa}B and release of the bound p65 and p50 subunits. The free NF-{kappa}B subunits translocate to the nucleus, dimerize, and bind NF-{kappa}B response elements to activate proinflammatory genes. The glucocorticoid receptor and the p65 subunit of NF-{kappa}B can physically interact and antago-nize each other's transcriptional activity. Several mechanisms have been proposed by which the physical interaction can lead to mutual antagonism: the glucocorticoid receptor and NF-{kappa}B may compete for coactivators SRC-1 (steroid receptor coactivator-1) and CBP (cAMP response element–binding protein [CREB]–binding protein) (direct binding coactivator competition); the cytoplasmic subunit of protein kinase A (PKA) may mediate the cross-repression of GR and NF-{kappa}B (PKA cross-talk); or the glucocorticoid receptor may directly or indirectly inhibit the phosphorylation and, thus, activity of RNA polymerase II (Pol II) on p65-occupied promoters (RNA Pol II inhibition). This GR-mediated inhibition prevents subsequent NF-{kappa}B–mediated gene transcription.

 
Given that NF-{kappa}B acts as a central mediator of inflammatory action in all cell types, it has been a major target for antiinflammatory small-molecule drugs. Many of the antiinflammatory actions of glucocorticoids are also attributed to the disruption of NF-{kappa}B function. The glucocorticoid receptor represses NF-{kappa}B transcriptional activity by physically interacting with the p65/RelA subunit (42, 43). The antagonism appears to be mutual, as p65 can inhibit GR-mediated transcription as well (Figure 4). The mutual antagonism requires multiple domains of the GR, including the DNA- and ligand-binding domains (42, 44). The nature of the GR-mediated repression of NF-{kappa}B transcription activity remains unclear and many mechanisms have been suggested (Figure 4). One mechanism suggests the mutual antagonism results from competition between the GR and p65 for limiting amounts of coactivators such as cAMP response element–binding protein (CREB)–binding protein required for maximal transcriptional activity (44, 45). However, one report argues against this competition theory and suggests antagonism occurs independently of coactivator levels within the cell (46). One study suggests GR prevents p65-induced transcription at the promoter level by interfering with phosphorylation of RNA polymerase II (47). In this mechanism, the p65 bound GR resides at the NF-{kappa}B response element and inhibits the serine-2 phosphorylation of RNA polymerase II, thus, preventing transcriptional initiation. Alternatively, the mutual antagonism between GR and NF-{kappa}B has been suggested to occur in the cytoplasm and not the nucleus. The cytoplasmic subunit of protein kinase A has been reported to mediate the cross-repression of GR and NF-{kappa}B (48). It remains possible that more than one mechanism exists or is cell type specific and further elucidation is required to understand the mutual antagonism between the transcription factors.

Inhibition of Mitogen-activated Protein Kinase Signaling
The mitogen-activated protein kinases (MAPKs) play a key role in inflammatory cell types through transducing the response from proinflammatory cytokine receptors to the transcriptional apparatus (49). MAPK subgroups such as JNK regulate activation of the AP-1 complex required for proinflammatory gene expression. The MAPK p38 subgroup regulates the stability of mRNAs that encode the proinflammatory molecules TNF-{alpha}, IL-6, IL-8, and vascular endothelial growth factor. Evidence suggests that negative regulation of the MAPK family by glucocorticoids may be an additional mechanism by which the GR may exert its antiinflammatory effects. The MAPK subgroups JNK, ERK1, ERK2, and p38 are all targets of negative regulation by glucocorticoids (39, 40, 49–54). For example, glucocorticoids destabilize the mRNA of the proinflammatory enzyme cyclooxygenase-2 by inhibiting the activity of mitogen-activated protein kinase p38 (54). In general, the glucocorticoid receptor represses the MAPK family by inhibiting the phosphorylation step required for their activation. The defined molecular mechanism behind this inhibition has not been fully characterized and may be cell type and stimulus specific. However, inhibition of p38 activity appears to result from a glucocorticoid-mediated induction of MKP-1 at the promoter level (51, 52).

Glucocorticoid-mediated Apoptosis of Inflammatory Cells
The antiinflammatory action of glucocorticoids also results from their ability to induce programmed cell death in inflammatory cell types such as thymocytes, monocytes, and eosinophils and to protect against apoptotic stimuli in other cells of nonlymphoid origin. The basis for susceptibility to apoptotic actions of glucocorticoids has not been fully characterized and may relate to the regulation of key pro/antiapoptotic genes in a cell-specific manner. The antiapoptotic effect of glucocorticoids in several cell types has been attributed to regulation of the antiapoptotic gene Bcl-2 and NF-{kappa}B signaling (55). In addition, it has been proposed that a fundamental requirement for glucocorticoid-mediated apoptosis is the level of endogenous GR protein within the cell (56). Glucocorticoid-mediated cell death appears to require a threshold level of GR protein. This level of GR is achieved in cells such as T lymphocytes, in which there is an apparent upregulation of glucocorticoid receptor levels (57). This is in contrast to most cell types, in which GR levels downregulate in response to glucocorticoids (58). A promoter of the GR-encoding gene that upregulates in response to glucocorticoids has been identified in T cells (3).

The mechanism of glucocorticoid-mediated apoptosis, as with other forms of apoptosis, is an extremely complex process of signaling cascades that remains incompletely characterized (reviewed in Ref. 59). Glucocorticoid-mediated apoptosis involves both the DNA-dependent and independent (transrepression) actions of glucocorticoid receptors. Briefly, glucocorticoids appear to induce apoptosis through a multiple-step process that begins with glucocorticoid receptor–mediated changes in gene expression through both transactivation and transrepression. Glucocorticoids repress transcription factors and cytokines required for survival of the cell through several mechanisms that involve repression of NF-{kappa}B and AP-1 signaling and regulation of antiapoptotic and proapoptotic Bcl-2 members. Expression of proapoptotic Bcl-2 members then triggers caspase activation, leading to cell death.

Synergism with Signal Transduction and Activator of Transcription Factors
The STAT family of transcription factors is also recognized as a key intracellular mediator of cytokine signaling. A range of cytokines activates STAT proteins through induction of the Janus kinase (JAK) pathway (Figure 5). Phosphorylation of the cytoplasmically localized monomeric forms of STAT proteins by JAKs induces their dimerization and translocation into the nucleus. The STAT proteins bind response elements and regulate a variety of genes that influence growth, survival, apoptosis, host defense, stress, and differentiation functions (60).



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  		Figure 5. Cross-talk between the glucocorticoid receptor and the STAT family. Cytokines such as IL-2 and IL-6 activate STAT proteins through induction of the Janus kinase (JAK) pathway. JAK phosphorylates STAT proteins that exist as monomers in the cytoplasm. JAK-mediated phosphorylation of STAT proteins induces their dimerization and translocation to the nucleus. The STAT proteins then bind response elements and regulate the expression of genes that influence growth, survival, apoptosis, host defense, stress, and differentiation functions. In some promoter contexts, the glucocorticoid receptor physically interacts with members of the STAT family such as STAT1, STAT3, and STAT5 (a and b), and synergistically enhances STAT-mediated gene expression. Reciprocally, STAT proteins can either enhance or repress GR-mediated gene activation depending on stimuli and the STAT protein involved.

 
The glucocorticoid receptor physically interacts with several members of the STAT family, including STAT1, STAT3, and STAT5 (a and b) (31–33, 61–64). The glucocorticoid receptor synergistically enhances STAT (STAT1, STAT3, and STAT5)-mediated activation of target genes in a promoter dependent fashion (Figure 5). In contrast, STAT proteins can either enhance or repress GR-mediated activation depending on stimuli and the STAT protein involved. For example, in response to IL-6, STAT3 and the GR synergistically activate the glucocorticoid responsive MMTV promoter and IL-6–responsive rat {gamma}-fibrinogen and {alpha}2-macroglobulin genes (31–33). In contrast, the interaction between the GR and IL-2–activated STAT5 results in antagonism of GR-mediated activation of the MMTV promoter but synergistic activation of the ß-casein gene (34, 61–63). Alternatively, the GR stimulated STAT1-dependent transcription of the Fc {gamma} receptor promoter, whereas STAT1 had no effect on GR-mediated activation of the MMTV promoter (64).

The functional interaction of STAT proteins with the GR does not appear to implicate a common effect on GR-mediated gene transcription. However, studies thus far have focused only on the effect of STATs on GR-mediated activation of the MMTV promoter and the impact on endogenous glucocorticoid-regulated genes remains unknown. In contrast, the GR appears to synergistically enhance transcription of numerous STAT-regulated promoters. The physiological relevance of such an action is unclear; however, emerging evidence suggests that glucocorticoids not only suppress but also enhance immune function by activating the expression of certain cytokine receptors. Synergism between STATs and the GR may be an alternative mechanism for enhancing immune function.

Expression of GRß in Glucocorticoid-resistant Inflammatory Diseases
Prolonged treatment of inflammatory diseases with glucocorticoids often leads to the development of glucocorticoid resistance states. Unfortunately, the molecular mechanisms responsible for the development of glucocorticoid resistance are poorly understood. However, there are an increasing number of studies that have suggested glucocorticoid resistance in inflammatory cell types is due to the expression of the dominant-negative hGRß isoform. High levels of hGRß protein have been observed in inflammatory lesions, peripheral blood mononuclear cells, and T cells of patients with glucocorticoid-insensitive asthma and colitis (6–8). In addition, proinflammatory cytokines such as TNF-{alpha} and IL-1 appear to upregulate hGRß in epithelial and lymphoid cell lines (9). The upregulation of hGRß levels depends on the presence of an NF-{kappa}B–binding site in the hGR promoter. Because hGRß can inhibit the actions of hGR{alpha}, increased expression of the dominant-negative hGRß in inflammatory cells may be a potential mechanism for ablating the antiinflammatory effects of glucocorticoids and inducing glucocorticoid resistance.

GR Cross-talk: A Balance Issue?
Both noninflammatory and inflammatory cell types express AP-1, NF-{kappa}B, and STAT transcription factors, which can have opposing actions to hGR{alpha}. Similarly, the glucocorticoid receptor has the potential for profound antagonistic effects on the activity of AP-1 and NF-{kappa}B within these same cells. What factors help determine the direction of antagonism between these proteins, if any, within a given cell? The answer to this question is complex and not completely known, and may in part depend on the specific cell type. One important factor in dictating antagonism may be the expression level of transcription factors within the cell. This relates to both the basal level of transcription factors within the cell and in response to ligands. GR expression levels downregulate in most cell types (58) in response to glucocorticoids, but appear to upregulate in lymphoid cell lines (57). Such differential expression could influence the probability of cross-talk on a cell type-specific basis. The transcriptional activities of AP-1, NF-{kappa}B, STAT, and the GR would also directly relate to the level of inducing stimuli. In an inflammatory cell expressing high levels of GR, in response to high levels of glucocorticoids the balance may tip in favor of the GR, resulting in antiinflammatory actions. Under glucocorticoid-resistant inflammatory conditions, the balance could be shifted the other way, for example, by overexpression of dominant-negative hGRß or NF-{kappa}B, AP-1, and STAT transcription factors. In support of this, one study implicates a role for STAT5 in IL-2–induced glucocorticoid resistance (65). Another major factor determining cross-talk within a cell is whether the various pathways are activated simultaneously and the duration of each response. This may be particularly applicable in noninflammatory cells, in which the cells may not be subjected to cytokine and glucocorticoid influences at the same time. In contrast to inflammatory cell types, our understanding of the occurrence and physiological significance of cross-talk between these pathways in noninflammatory cell remains elusive.


   ACKNOWLEDGMENTS
 
B.M.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form February 17, 2004; accepted in final form March 30, 2004)


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