Reciprocal relation between GADD153 and Del-1 in regulation of salivary gland inflammation in Sjögren syndrome

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Endoplasmic reticulum (ER) stress response is a pivotal regulator of inflammation and cell death. An integral component of ER stress-induced apoptosis is expression of growth arrest- and DNA damage-inducible protein 153 (GADD153). Further, ER stress response is implicated in leukocyte adhesion and recent studies have discovered endogenous inhibitors of leukocyte adhesion including the developmental endothelial locus-1 (Del-1). Accordingly, we tested the hypothesis that Sjögren's syndrome (SS) is associated with increased salivary gland expression of GADD153 and increased leukocyte infiltration in association with decreased Del-1 thereby contributing to inflammation and cell death. We utilized the non-obese diabetic (NOD) mice, a model of SS-like disease, in association with immunostaining and flow cytometry-based studies. Salivary glands of 14-week-old NOD mice displayed a) increased GADD153 expression, b) marked reduction in Del-1, c) inflammatory cell infiltrates including CD3. + T and CD19. + B lymphocytes as well as M1 and M2 macrophages and d) increased pro-inflammatory interleukin (IL)-17 but reduced anti-inflammatory cytokine, IL-10. These changes were accompanied with disruption of mitochondrial membrane potential and significant increase in apoptosis and necrosis of salivary gland cells of NOD than control mice. Our collective observations suggested that GADD153 directly and/or indirectly through downregulation of Del-1 contributes importantly to salivary gland inflammation and cell death. To establish the relevance of GADD153 and Del-1 for the human condition, lower lip biopsy samples of non-SS subjects and those with a diagnosis of SS were subjected to immunohistochemistry. The results show intense GADD153 immunostaining but marked reduction in Del-1 expression in biopsy samples of SS compared to non-SS subjects. Collectively, the results indicate that GADD153 regulates inflammation and cell death in salivary gland in SS. Further, Del-1 expression likely provides a mechanistic link between increased GADD153 and leukocyte infiltration and accompanying inflammation of salivary gland tissue in this condition.

Original languageEnglish (US)
Pages (from-to)288-297
Number of pages10
JournalExperimental and Molecular Pathology
Issue number3
StatePublished - Dec 2013


  • Cell death
  • Del-1
  • GADD153
  • Immune cells
  • Inflammation
  • Lower lip biopsy
  • Salivary gland
  • Sjögren syndrome

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Clinical Biochemistry


Dive into the research topics of 'Reciprocal relation between GADD153 and Del-1 in regulation of salivary gland inflammation in Sjögren syndrome'. Together they form a unique fingerprint.

Cite this