| First Author | Hoppstädter J | Year | 2015 |
| Journal | J Immunol | Volume | 194 |
| Issue | 12 | Pages | 6057-67 |
| PubMed ID | 25964494 | Mgi Jnum | J:292576 |
| Mgi Id | MGI:6448026 | Doi | 10.4049/jimmunol.1403207 |
| Citation | Hoppstadter J, et al. (2015) Glucocorticoid-induced leucine zipper: a critical factor in macrophage endotoxin tolerance. J Immunol 194(12):6057-67 |
| abstractText | 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-alpha and IL-1beta 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. |
