Glucocorticoid-induced leucine zipper (GILZ) is transcriptionally up-regulated by glucocorticoids (GCs) and mediates many of the anti-inflammatory effects of GCs. GILZ is an important regulator of B cell survival and homeostasis. B cells modulate the inflammatory responses in the gut, and B cell activity has been linked to cytokine production and modulation of inflammatory responses; however the role and the mechanisms of B cell activity in inflammatory bowel diseases is unclear. In this context, we investigated the role of GILZ in B cells during colitis development. B cell-specific gilz knock-out (gilz B cKO) mice exhibited overproduction of the pro-inflammatory cytokine IFN-γ in B cells, and an increased CD4+ T cell activation. Increased IFN-γ production in B cells in gilz B cKO mice was associated with enhanced transcriptional activity of Activator Protein 1 (AP1) on the IFN-γ promoter. Moreover, GILZ deficiency in B cells exacerbates colitis in mice, and in vivo administration of GILZ fusion protein counters colitis. Interestingly, the increased production of IFN-γ was observed also in T cells infiltrating the lamina propria of gilz B cKO mice. Altogether, our findings demonstrate that GILZ controls IFN-γ production by B cells, and its disruption in mice results in increased IFN-γ production by B and T cells in colon lamina propria, which results in predisposition to inflammatory colitis. Therefore, modulation of GILZ expression could be used as a new therapeutic strategy for the treatment of inflammatory bowel diseases.

B lymphocytes and inflammation: role of Glucocorticoid-induced leucine zipper

Bereshchenko O
Membro del Collaboration Group
;
Migliorati G
Membro del Collaboration Group
;
Bruscoli S
Membro del Collaboration Group
;
2019-01-01

Abstract

Glucocorticoid-induced leucine zipper (GILZ) is transcriptionally up-regulated by glucocorticoids (GCs) and mediates many of the anti-inflammatory effects of GCs. GILZ is an important regulator of B cell survival and homeostasis. B cells modulate the inflammatory responses in the gut, and B cell activity has been linked to cytokine production and modulation of inflammatory responses; however the role and the mechanisms of B cell activity in inflammatory bowel diseases is unclear. In this context, we investigated the role of GILZ in B cells during colitis development. B cell-specific gilz knock-out (gilz B cKO) mice exhibited overproduction of the pro-inflammatory cytokine IFN-γ in B cells, and an increased CD4+ T cell activation. Increased IFN-γ production in B cells in gilz B cKO mice was associated with enhanced transcriptional activity of Activator Protein 1 (AP1) on the IFN-γ promoter. Moreover, GILZ deficiency in B cells exacerbates colitis in mice, and in vivo administration of GILZ fusion protein counters colitis. Interestingly, the increased production of IFN-γ was observed also in T cells infiltrating the lamina propria of gilz B cKO mice. Altogether, our findings demonstrate that GILZ controls IFN-γ production by B cells, and its disruption in mice results in increased IFN-γ production by B and T cells in colon lamina propria, which results in predisposition to inflammatory colitis. Therefore, modulation of GILZ expression could be used as a new therapeutic strategy for the treatment of inflammatory bowel diseases.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1461273
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