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Glucocorticoids (GCs) are steroid hormones produced by the adrenal gland and regulated by the hypothalamus-pituitary-adrenal axis. GCs mediate effects that mostly result in transcriptional regulation of glucocorticoid receptor target genes. Mitogen-activated protein kinases (MAPKs) comprise a family of signaling proteins that convert extracellular stimuli into the activation of intracellular transduction pathways via phosphorylation of a cascade of substrates. They modulate a variety of physiological cell processes, such as proliferation, apoptosis, and development. However, when MAPKs are improperly activated by proinflammatory and/or extracellular stress stimuli, they contribute to the regulation of proinflammatory transcription factors, thus perpetuating activation of the inflammatory cascade. One of the mechanisms by which GCs exert their anti-inflammatory effects is negative interference with MAPK signaling pathways. Several functional interactions between GCs and MAPK signaling have been discovered and studied. Some of these interactions involve the GC-mediated up-regulation of proteins that in turn interfere with the activation of MAPK, such as glucocorticoid-induced-leucine zipper, MAPK phosphatase-1, and annexin-1. Other mechanisms include activated GR directly interacting with components of the MAPK pathway and negatively regulating their activation. The multiple interactions between GCs and MAPK pathways and their potential biological relevance in mediating the anti-inflammatory effects of GCs are reviewed.

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Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous genes. GILZ (glucocorticoidinduced leucine zipper), being one of them, is strongly up-regulated in the thymus. To elucidate its function we generated transgenic mice overexpressing it specifically in the T-cell lineage and characterized its influence on thymus function. In young adult transgenic mice CD4 ؉ CD8 ؉ thymocyte number was significantly decreased and ex vivo thymocyte apoptosis was increased. Apoptotic pathway analysis detected reduced antiapoptotic B-cell leukemia XL (Bcl-xL) expression and increased activation of caspase-8 and caspase-3. Time-course experiments showed that in wild-type (WT) thymocytes GILZ up-regulation was followed by sequential Bcl-xL decreased expression and activation of caspase-8 and of caspase-3. Moreover, GILZ delivered inside WT thymocytes by a fusion protein with the transactivator of transcription (TAT) peptide decreased Bcl-xL and promoted their apoptosis. In aged mice perturbation of thymic subset numbers was amplified over time, as demonstrated by a further decrease in CD4 ؉ CD8 ؉ cells and increases in CD4 ؉ CD8 ؊ , CD4 ؊ CD8 ؊ , and CD8 ؉ CD4 ؊ cell counts. These results support the hypothesis that GILZ participates in the regulation of thymocyte apoptosis by glucocorticoids. IntroductionGlucocorticoids (GCs) are hormones and drugs that express their functions by binding and activating their specific intracellular receptor (GR), thus acting through genomic and nongenomic mechanisms. The thymus, one of their target organs, promotes thymocyte maturation to functional CD4 ϩ or CD8 ϩ single positive (SP) T lymphocytes that are ready to migrate to the periphery. T-cell development in the thymus is ordered by sequential steps that involve waves of cell proliferation and apoptosis. Apoptosis is a key process in thymus physiology and is triggered in 3 well-known ways: (1) negative selection, involving 5% of all thymocytes, eliminates autoreactive T-cell clones at the level of CD4 ϩ CD8 ϩ double-positive (DP) cells; (2) death by neglect involves 90% of DP thymocytes that are neither positively nor negatively selected; and (3) stress-induced cell death. 1 GCs promote apoptosis of DP thymocytes 2 but are not involved in apoptosis by negative selection. 3 Their role in apoptosis by neglect is uncertain, but they certainly mediate stress-induced apoptosis. 1 The apoptotic signaling pathway triggered by the synthetic GC dexamethasone (DEX) in thymocytes has recently been clarified to some extent. The GC receptor coordinates activation of gene transcription and caspase-8, -9, and -3 in a sequence that leads to thymocyte apoptosis. [4][5][6][7] Additionally, GC-mediated thymic apoptosis is regulated by many different molecules, and the B-cell leukemia 2 (Bcl-2) family of proteins is a critical regulator of apoptosis. 8 The family is subdivided into antiapoptotic members such as Bcl-2 and Bcl-xL, and proapoptotic members such as Bcl-2-associated X protein (Bax) and BCL-2 homologous antagonist/killer (Ba...

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Glucocorticoids (GCs), important therapeutic tools to treat inflammatory and immunosuppressive diseases, can also be used as part of cancer therapy. In oncology, GCs are used as anticancer drugs for lymphohematopoietic malignancies, while in solid neoplasms primarily to control the side effects of chemo/radiotherapy treatments. The molecular mechanisms underlying the effects of GCs are numerous and often overlapping, but not all have been elucidated. In normal, cancerous, and inflammatory tissues, the response to GCs differs based on the tissue type. The effects of GCs are dependent on several factors: the tumor type, the GC therapy being used, the expression level of the glucocorticoid receptor (GR), and the presence of any other stimuli such as signals from immune cells and the tumor microenvironment. Therefore, GCs may either promote or suppress tumor growth via different molecular mechanisms. Stress exposure results in dysregulation of the hypothalamic–pituitary–adrenal axis with increased levels of endogenous GCs that promote tumorigenesis, confirming the importance of GCs in tumor growth. Most of the effects of GCs are genomic and mediated by the modulation of GR gene transcription. Moreover, among the GR-induced genes, glucocorticoid-induced leucine zipper (GILZ), which was cloned and characterized primarily in our laboratory, mediates many GC anti-inflammatory effects. In this review, we analyzed the possible role for GILZ in the effects GCs have on tumors cells. We also suggest that GILZ, by affecting the immune system, tumor microenvironment, and directly cancer cell biology, has a tumor-promoting function. However, it may also induce apoptosis or decrease the proliferation of cancer cells, thus inhibiting tumor growth. The potential therapeutic implications of GILZ activity on tumor cells are discussed here.

Glucocorticoid-induced leucine zipper (GILZ) is a protein with multiple biological roles that is upregulated by glucocorticoids (GCs) in both immune and non-immune cells. Importantly, GCs are immunosuppressive primarily due to their regulation of cell signaling pathways that are crucial for immune system activity. GILZ, which is transcriptionally induced by the glucocorticoid receptor (GR), mediates part of these immunosuppressive, and anti-inflammatory effects, thereby controlling immune cell proliferation, survival, and differentiation. The primary immune cells targeted by the immunosuppressive activity of GCs are T cells. Importantly, the effects of GCs on T cells are partially mediated by GILZ. In fact, GILZ regulates T-cell activation, and differentiation by binding and inhibiting factors essential for T-cell function. For example, GILZ associates with nuclear factor-κB (NF-κB), c-Fos, and c-Jun and inhibits NF-κB-, and AP-1-dependent transcription. GILZ also binds Raf and Ras, inhibits activation of Ras/Raf downstream targets, including mitogen-activated protein kinase 1 (MAPK1). In addition GILZ inhibits forkhead box O3 (FoxO3) without physical interaction. GILZ also promotes the activity of regulatory T cells (Tregs) by activating transforming growth factor-β (TGF-β) signaling. Ultimately, these actions inhibit T-cell activation and modulate the differentiation of T helper (Th)-1, Th-2, Th-17 cells, thereby mediating the immunosuppressive effects of GCs on T cells. In this mini-review, we discuss how GILZ mediates GC activity on T cells, focusing mainly on the therapeutic potential of this protein as a more targeted anti-inflammatory/immunosuppressive GC therapy.