Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice.
Glucocorticoids (GC) are widely used as antiinflammatory/immunosuppressive drugs and antitumor agents in several types of lymphoma and leukemia. Therapeutic doses of GC induce growth-suppressive and cytotoxic effects on various leukocytes including B cells. Molecular mechanisms of GC action include induction of GC target genes. Glucocorticoid-induced leucine zipper (GILZ) is a rapidly, potently, and invariably GC-induced gene. It mediates a number of GC effects, such as control of cell proliferation, differentiation, and apoptosis. Here we show that deletion of GILZ in mice leads to an accumulation of B lymphocytes in the bone marrow, blood, and lymphoid tissues. Gilz knockout (KO) mice develop a progressive nonlethal B lymphocytosis, with expansion of B220(+) cells in the bone marrow and in the periphery, dependent on increased B-cell survival. Decreased B-cell apoptosis in mice lacking GILZ correlates with increased NF-κB transcriptional activity and Bcl-2 expression. B cell-specific gilz KO mice confirmed that the effect of GILZ deletion is B-cell self-intrinsic. These results establish GILZ as an important regulator of B-cell survival and suggest that the deregulation of GILZ expression could be implicated in the pathogenesis of B-cell disorders.
Department of Medicine, Section of Pharmacology and.
Stefano
http://orcid.org/0000-0003-0313-1615
S
Bruscoli
Department of Medicine, Section of Pharmacology and.
Michele
M
Biagioli
Department of Medicine, Section of Pharmacology and.
Daniele
D
Sorcini
Department of Medicine, Section of Pharmacology and.
Tiziana
T
Frammartino
Department of Medicine, Section of Pharmacology and.
Monica
M
Cimino
Department of Medicine, Section of Hematology, University of Perugia, Perugia, Italy; and.
Paolo
P
Sportoletti
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro Neurolesi "Bonino-Pulejo," Messina, Italy.
Emanuela
E
Mazzon
Department of Medicine, Section of Pharmacology and.
Oxana
O
Bereshchenko
Department of Medicine, Section of Pharmacology and.
Carlo
C
Riccardi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000473:pathology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology*; D008218:Lymphocytosis / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*
C498608:Dsip1 protein, mouse; D005938:Glucocorticoids; D012333:RNA, Messenger; D014157:Transcription Factors