Glucocorticoid-induced leucine zipper: a critical factor in macrophage endotoxin tolerance.
J Immunol
; 194(12): 6057-67, 2015 Jun 15.
Article
em En
| MEDLINE
| ID: mdl-25964494
ABSTRACT
Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a key role in their anti-inflammatory action. In activated macrophages, GILZ levels are downregulated via tristetraprolin-mediated GILZ mRNA destabilization. To assess the functional significance of GILZ downregulation, we generated myeloid-specific GILZ knockout (KO) mice. GILZ-deficient macrophages displayed a higher responsiveness toward LPS, as indicated by increased TNF-α and IL-1ß expression. This effect was due to an activation of ERK, which was significantly amplified in GILZ KO cells. The LPS-induced activation of macrophages is attenuated upon pretreatment of macrophages with low-dose LPS, an effect termed endotoxin tolerance. In LPS-tolerant macrophages, GILZ mRNA was stabilized, whereas ERK activation was strongly decreased. In contrast, GILZ KO macrophages exhibited a strongly reduced desensitization. To explore the contribution of GILZ expression in macrophages to endotoxin tolerance in vivo, we treated GILZ KO mice with repeated i.p. injections of low-dose LPS followed by treatment with high-dose LPS. LPS pretreatment resulted in reduced proinflammatory mediator expression upon high-dose LPS treatment in serum and tissues. In contrast, cytokine induction was preserved in tolerized GILZ KO animals. In summary, our data suggest that GILZ is a key regulator of macrophage functions.
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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Endotoxinas
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Tolerância Imunológica
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Macrófagos
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2015
Tipo de documento:
Article