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<p>The Glucocorticoid-Induced Leucine Zipper (GILZ) is a key mediator of the anti-inflammatory effects of glucocorticoids, primarily within the immune system. Recent evidence has implicated GILZ as a secretive protein in goblet cells, with reduced expression linked to active Inflammatory Bowel Disease (IBD), suggesting a role in intestinal cell homeostasis. In this context, GILZ has been found also in enteroendocrine cells (EEC), but its role remained undefined. This study aimed at identifying GILZ-expressing EEC subtypes, dissecting how the secretive function is affected by inflammation in human ulcerative colitis (UC) and exploring its role in these cells. GILZ was predominantly expressed in glucagon-like-peptide-1 (GLP-1)-secreting L-cells, across all stages of EEC differentiation. GILZ was also expressed in serotonin (5HT)-producing enterochromaffin cells (EC), even though at low levels. Such an expression profile was supported by analysis of publicly available single-cell RNA sequencing datasets, identifying both EEC progenitors and mature subsets. Interestingly, confocal immunofluorescence localized GILZ to cytoplasmic granules partially co-staining with GLP-1-containing vesicles. Histological analysis of mucosal colonic biopsies revealed a global reduction in EEC during active UC as compared to healthy individuals and quiescent UC. Specifically, GILZ-expressing L-cells were significantly reduced in active UC and only partially restored in quiescent disease. In contrast, 5HT-producing EC cells were still reduced during active UC but fully recovered in quiescent disease. In vitro, NCI-H716 L-cell line-secreted products reduced IL-8 secretion in Caco2 epithelial cells, indicating an anti-inflammatory effect. This activity was attenuated following GILZ silencing. Interestingly, treatment with a recombinant TAT-GILZ protein directly diminished IL-8 in Caco2 cells. Collectively, our findings identify GILZ as a novel secretory product of L-cells with potential anti-inflammatory properties. Restoring GILZ secretion may represent a promising therapeutic strategy to mitigate chronic intestinal inflammation in UC.</p>

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Glucocorticoid-induced Leucine Zipper (GILZ) is a novel secreted protein by intestinal L-cells and is dysregulated during active ulcerative colitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Lucrezia Rosati,
  • Giuseppe Leoncini,
  • Luigi Cari,
  • Maria Rosaria Sette,
  • Martina Procaccini,
  • Giuseppe Nocentini,
  • Vincenzo Villanacci,
  • Carlo Riccardi,
  • Graziella Migliorati,
  • Simona Ronchetti

摘要

The Glucocorticoid-Induced Leucine Zipper (GILZ) is a key mediator of the anti-inflammatory effects of glucocorticoids, primarily within the immune system. Recent evidence has implicated GILZ as a secretive protein in goblet cells, with reduced expression linked to active Inflammatory Bowel Disease (IBD), suggesting a role in intestinal cell homeostasis. In this context, GILZ has been found also in enteroendocrine cells (EEC), but its role remained undefined. This study aimed at identifying GILZ-expressing EEC subtypes, dissecting how the secretive function is affected by inflammation in human ulcerative colitis (UC) and exploring its role in these cells. GILZ was predominantly expressed in glucagon-like-peptide-1 (GLP-1)-secreting L-cells, across all stages of EEC differentiation. GILZ was also expressed in serotonin (5HT)-producing enterochromaffin cells (EC), even though at low levels. Such an expression profile was supported by analysis of publicly available single-cell RNA sequencing datasets, identifying both EEC progenitors and mature subsets. Interestingly, confocal immunofluorescence localized GILZ to cytoplasmic granules partially co-staining with GLP-1-containing vesicles. Histological analysis of mucosal colonic biopsies revealed a global reduction in EEC during active UC as compared to healthy individuals and quiescent UC. Specifically, GILZ-expressing L-cells were significantly reduced in active UC and only partially restored in quiescent disease. In contrast, 5HT-producing EC cells were still reduced during active UC but fully recovered in quiescent disease. In vitro, NCI-H716 L-cell line-secreted products reduced IL-8 secretion in Caco2 epithelial cells, indicating an anti-inflammatory effect. This activity was attenuated following GILZ silencing. Interestingly, treatment with a recombinant TAT-GILZ protein directly diminished IL-8 in Caco2 cells. Collectively, our findings identify GILZ as a novel secretory product of L-cells with potential anti-inflammatory properties. Restoring GILZ secretion may represent a promising therapeutic strategy to mitigate chronic intestinal inflammation in UC.