Glucocorticoid-induced leucine zipper (GILZ) over-expression in T lymphocytes inhibits inflammation and tissue damage in spinal cord injury

Neurotherapeutics. 2012 Jan;9(1):210-25. doi: 10.1007/s13311-011-0084-7.

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 anti-inflammatory 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 glucocorticoid-induced 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cyclin D1 / metabolism
  • Cytokines / metabolism
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Glial Fibrillary Acidic Protein / metabolism
  • In Situ Nick-End Labeling
  • Inflammation / etiology*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Mice
  • Mice, Transgenic
  • Nitric Oxide Synthase Type II / metabolism
  • Peroxidase / metabolism
  • Signal Transduction / genetics
  • Spinal Cord Injuries / complications*
  • Spinal Cord Injuries / pathology
  • T-Lymphocytes / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Cytokines
  • Dsip1 protein, mouse
  • Glial Fibrillary Acidic Protein
  • Transcription Factors
  • bcl-2-Associated X Protein
  • Cyclin D1
  • Peroxidase
  • Nitric Oxide Synthase Type II
  • Dinoprostone