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 GMembro del Collaboration Group
;Bruscoli SMembro del Collaboration Group
;
2019
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
