Recombinant long-glucocorticoid-induced leucine zipper (L-GILZ) protein restores the control of proliferation in gilz KO spermatogonia

Venanzi, Alessandra; Sante, Moises Di; Bruscoli, Stefano; Biagioli, Michele; Sorcini, Daniele; Cimino, Monica; Frammartino, Tiziana; Bereshchenko, Oxana; Franconi, Flavia; Riccardi, Carlo

doi:10.1016/j.ejps.2014.06.013

Cited by 12 publications

(14 citation statements)

References 29 publications

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“…Gilz deficiency in knock‐out mice shows a complete loss of germ cell lineage within the first cycles of spermatogenesis, resulting in male sterility, but no abnormalities in the immune system, adipogenesis, or sodium reabsorption . In addition, a recent report demonstrates that recombinant GILZ protein restores the control of proliferation in spermatogonia of Gilz knock‐out mice and re‐activation of GILZ has a potential for new therapeutic strategies . Moreover, previous studies have shown that NR3C1 / GR mutations or polymorphisms are associated with glucocorticoid resistance and obesity .…”

Section: Discussionmentioning

confidence: 99%

Association of NR3C1/Glucocorticoid Receptor gene SNP with azoospermia in Japanese men

Chihara

Yoshihara

Ishiguro

et al. 2015

J of Obstet and Gynaecol

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Section: Discussionmentioning

confidence: 99%

Association of NR3C1/Glucocorticoid Receptor gene SNP with azoospermia in Japanese men

Chihara

Yoshihara

Ishiguro

et al. 2015

J of Obstet and Gynaecol

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“…In addition to its ability to bind to NF-kB and AP-1, GILZ has also been reported to interfere with MAPK signaling (3,7,8,23,30,31). MAPKs modulate various physiological cell processes, such as proliferation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…GILZ has been suggested to modulate MAPK signaling in various cell types (3,7,8,23,30,31). Therefore, we examined LPS-induced p38, JNK, and ERK activation in WT and GILZ KO cells.…”

Section: Sensitization Of Gilz Ko Macrophages Toward Lps Is Facilitatmentioning

confidence: 99%

Glucocorticoid-Induced Leucine Zipper: A Critical Factor in Macrophage Endotoxin Tolerance

Hoppstädter

Kessler

Bruscoli

et al. 2015

The Journal of Immunology

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Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a key role in their anti-inflammatory action. In activated macrophages, GILZ levels are downregulated via tristetraprolin-mediated GILZ mRNA destabilization. To assess the functional significance of GILZ downregulation, we generated myeloid-specific GILZ knockout (KO) mice. GILZ-deficient macrophages displayed a higher responsiveness toward LPS, as indicated by increased TNF-α and IL-1β expression. This effect was due to an activation of ERK, which was significantly amplified in GILZ KO cells. The LPS-induced activation of macrophages is attenuated upon pretreatment of macrophages with low-dose LPS, an effect termed endotoxin tolerance. In LPS-tolerant macrophages, GILZ mRNA was stabilized, whereas ERK activation was strongly decreased. In contrast, GILZ KO macrophages exhibited a strongly reduced desensitization. To explore the contribution of GILZ expression in macrophages to endotoxin tolerance in vivo, we treated GILZ KO mice with repeated i.p. injections of low-dose LPS followed by treatment with high-dose LPS. LPS pretreatment resulted in reduced proinflammatory mediator expression upon high-dose LPS treatment in serum and tissues. In contrast, cytokine induction was preserved in tolerized GILZ KO animals. In summary, our data suggest that GILZ is a key regulator of macrophage functions.

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“…Results indicate that p65/NF-kB binds more to the Bcl-2 promoter in purified B cells lacking GILZ ( Figure 6G). Of note, other pathways inhibited by GILZ in other cell types, such as ERK and Akt, 18,35 were not enhanced in gilz-deficient B cells, stimulated or not by anti-IgM antibody, compared with controls (supplemental Figure 7). These data indicate that lack of GILZ results in increased NF-kB nuclear translocation and transcriptional activity, leading to an increase in Bcl-2 expression and B-cell survival.…”

Section: Lack Of Gilz Inhibits Spontaneous B-cell Apoptosismentioning

confidence: 99%

Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice

Bruscoli¹,

Biagioli²,

Sorcini³

et al. 2015

Blood

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Key Points• GILZ-deficient mice develop B-cell lymphocytosis.• GILZ deficiency precludes GC-mediated B-cell apoptosis.Glucocorticoids (GC) are widely used as antiinflammatory/immunosuppressive drugs and antitumor agents in several types of lymphoma and leukemia. Therapeutic doses of GC induce growth-suppressive and cytotoxic effects on various leukocytes including B cells. Molecular mechanisms of GC action include induction of GC target genes. Glucocorticoidinduced leucine zipper (GILZ) is a rapidly, potently, and invariably GC-induced gene. It mediates a number of GC effects, such as control of cell proliferation, differentiation, and apoptosis. Here we show that deletion of GILZ in mice leads to an accumulation of B lymphocytes in the bone marrow, blood, and lymphoid tissues. Gilz knockout (KO) mice develop a progressive nonlethal B lymphocytosis, with expansion of B220 1 cells in the bone marrow and in the periphery, dependent on increased B-cell survival. Decreased B-cell apoptosis in mice lacking GILZ correlates with increased NF-kB transcriptional activity and Bcl-2 expression. B cell-specific gilz KO mice confirmed that the effect of GILZ deletion is B-cell self-intrinsic. These results establish GILZ as an important regulator of B-cell survival and suggest that the deregulation of GILZ expression could be implicated in the pathogenesis of B-cell disorders. (Blood. 2015;126(15):1790-1801

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Recombinant long-glucocorticoid-induced leucine zipper (L-GILZ) protein restores the control of proliferation in gilz KO spermatogonia

Cited by 12 publications

References 29 publications

Association of NR3C1/Glucocorticoid Receptor gene SNP with azoospermia in Japanese men

Association of NR3C1/Glucocorticoid Receptor gene SNP with azoospermia in Japanese men

Glucocorticoid-Induced Leucine Zipper: A Critical Factor in Macrophage Endotoxin Tolerance

Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice

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