Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is a traumatic event that causes a secondary and extended inflammation characterized by infiltration of immune cells, including T lymphocytes, release of pro-inflammatory mediators in the lesion site, and tissue degeneration. Current therapeutic approaches for SCI are limited to glucocorticoids (GC) due to their potent antiinflammatory activity. GC efficacy resides, in part, in the capability to inhibit NF-κB, T lymphocyte activation, and the consequent cytokine production. In this study, we performed experiments aimed to test the susceptibility of glucocorticoidinduced leucine zipper (GILZ) transgenic (GILZ TG ) mice, in which GILZ is selectively over-expressed in T lymphocytes, to SCI induction. Consistent with a decreased inflammatory response, GILZ TG were less susceptible to SCI as compared to wild-type littermates. Notably, inhibition of NF-κB activation and nuclear translocation, diminished T lymphocytes activation and tissue infiltration, as well as decreased release of cytokines were evident in GILZ TG as compared to wild-type mice. Moreover, GILZ TG showed a reduced tumor necrosis factor-α, IL-1β, Inductible nitric oxide synthase (iNOS) and nytrotyrosine production, apoptosis, and neuronal tissue damage. Together these results indicate that GILZ mimics the anti-inflammatory effect of GC and represents a potential pharmacological target for modulation of T lymphocyte-mediated immune response in inflammatory disorders, such as SCI.

The Role and Effects of Glucocorticoid-Induced Leucine Zipper in the Context of Inflammation Resolution

“…Indeed, in more complex models of inflammation where TAT-GILZ was used it was an effective strategy to control inflammation. For instance, TAT-GILZ administration promoted a protective effect in a model of inflammatory bowel disease (9) and spinal cord injury (12). Moreover, recent studies showed that GILZ overexpression inhibits endothelial cell adhesion function (42) and protects against endotoxemia (43) and arthritis (13).…”

“…These mechanisms are thought to be important for their ability to attenuate inflammation (8). GILZ appears to have a physiological role in the regulation of inflammatory mechanisms; however, there are few reports that explore its role in inflammatory disease (9)(10)(11)(12)(13).…”

Effects of propofol and etomidate pretreatment on glucocorticoid receptor expression following induction of sepsis in rats

“…Therefore, the rescue of sepsis through propofol use in the clinic still had great theoretical risk. Many other drugs can also be used for anti-inflammation effects; thus, the clinical application of propofol still lacks powerful physiological and pharmacological support (Esposito et al, 2012). Considering the question of cardiovascular safety, etomidate has received more attention for its reduced impact on cardiovascular function and stable hemodynamics (He et al, 2012).…”

Anti-inflammatory and anti-apoptotic effect of Rhodiola crenulata extract on spinal cord injury in rats

“…Spinal cord sections from control-and RCE-treated animals were stained as a set to compare identically processed tissue. The slices were observed under a microscope by blinded investigators who scored the samples on a scale of 0-4 for oedema, where 0 indicates no or minor levels of neutrophil infiltration and haemorrhage; 1 indicates modest or limited, 2 indicates intermediate, 3 indicates widespread or prominent, and 4 indicates widespread and highly prominent levels [1,17].…”