Glucocorticoid-Induced Leucine Zipper: A Promising Marker for Monitoring and Treating Sepsis

He, Yan-Ling; Xu, Jiqian; Sun, Mingshen; Fang, Xiangzhi; Peng, Zhe-Kang; Pan, Shangwen; Zhou, Ting; Wang, Yaxin; Shang, You

doi:10.3389/fimmu.2020.606649

Cited by 7 publications

(7 citation statements)

References 96 publications

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“…In contrast with the GRα, expression of GILZ, a well-known GR target gene and marker of genomic action hereof, 45 was only robustly suppressed in neutrophils but not in other cell or tissue types. In contrast, GILZ expression was upregulated during critical illness in monocytes, skeletal muscle and diaphragm, heart, lung, kidney and liver, a finding that strongly advocates against presence of total glucocorticoid resistance within these target tissues.…”

Section: Discussionmentioning

confidence: 87%

Impact of duration of critical illness and level of systemic glucocorticoid availability on tissue-specific glucocorticoid receptor expression and actions: A prospective, observational, cross-sectional human and two translational mouse studies

et al. 2022

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Section: Discussionmentioning

confidence: 87%

Impact of duration of critical illness and level of systemic glucocorticoid availability on tissue-specific glucocorticoid receptor expression and actions: A prospective, observational, cross-sectional human and two translational mouse studies

et al. 2022

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“…An opposite effect of GILZ was observed in oxazolone-induced colitis which is a Th2-dependent model of chronic inflammation where more severe disease was induced in mice overexpressing GILZ compared to the wild type mice suggesting that GILZ could have a protective role in Th1-mediated models of colitis ( 41 ). Further validation studies will help to explore the promising role of GILZ as marker of GC response in IBD patients as already proposed for other pathologies ( 43 , 44 ) evaluating its levels also in the blood cells to avoid an invasive examination.…”

Section: Discussionmentioning

confidence: 99%

Gender May Influence the Immunosuppressive Actions of Prednisone in Young Patients With Inflammatory Bowel Disease

et al. 2021

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Although the use of glucocorticoids (GC) is well established, the therapeutic response to these agents often shows important interindividual differences, in particular among young patients with inflammatory bowel diseases (IBD). Currently, GC resistance or dependence cannot be predicted by clinical or laboratory findings. The aim of this study was to investigate the association of gender and age with GC efficacy and with the expression of Glucocorticoid-Induced Leucine Zipper (GILZ). One hundred thirty patients (mean age at enrolment 12.6 years, 53 Crohn’s disease, 70 males) were enrolled in this retrospective study. IBD patients with active disease despite prednisone at a daily dose of up to 2 mg/kg over a period of 4 weeks were defined as steroid resistant. Patients who initially responded but relapsed upon dose reduction were considered steroid-dependent. Total RNA was extracted from biopsies of 14 patients (9 males) and the levels of GILZ mRNA were evaluated by real-time PCR. Association between clinical response to prednisone and the considered demographic variables was evaluated using logistic regression models. After 4 weeks of treatment, 112 patients were responders to prednisone and 18 were resistant; at this time-point, resistant patients were older than responders (p=0.032). After 12 weeks, 42, 71 and 12 patients were sensitive, dependent and resistant respectively; at this time-point, females were more prone than males to develop prednisone dependence vs a good response (p=0.028) while age had no effect. Age was associated with response both at 4 and 12 weeks in the subgroups of females: resistant patients were older than sensitive ones at 4 weeks (p=0.02). Likewise, at 12 weeks of therapy, dependent patients resulted older than sensitive ones (p=0.05). No association of age with prednisone response was found in males. In a subgroup of 14 patients (5 females), GILZ mRNA expression in intestinal biopsies was higher in males (p=0.0031). Patients with unfavorable response (7) presented lower GILZ expression at disease onset in comparison to the responder group (p=0.017). Older females with IBD have a higher incidence of prednisone unfavorable response and reduced intestinal expression of the GC pharmacodynamic marker GILZ.

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“…Sepsis is a complex disease where generalized systemic inflammation and tissue damage lead to multiple organ failure and death. Sepsis is considered a global health priority with estimates around 30 million patients, and mortality rates around 30-50% annually [143]. In sepsis patients, the impaired inflammatory response transitions from excessive to immunosuppressive stages.…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways

Sevilla

Jiménez-Panizo

Alegre-Martí

et al. 2021

IJMS

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Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential.

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Glucocorticoid-Induced Leucine Zipper: A Promising Marker for Monitoring and Treating Sepsis

Cited by 7 publications

References 96 publications

Impact of duration of critical illness and level of systemic glucocorticoid availability on tissue-specific glucocorticoid receptor expression and actions: A prospective, observational, cross-sectional human and two translational mouse studies

Impact of duration of critical illness and level of systemic glucocorticoid availability on tissue-specific glucocorticoid receptor expression and actions: A prospective, observational, cross-sectional human and two translational mouse studies

Gender May Influence the Immunosuppressive Actions of Prednisone in Young Patients With Inflammatory Bowel Disease

Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways

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