| First Author | Kim GD | Year | 2017 |
| Journal | Mol Cell Biol | PubMed ID | 29203644 |
| Mgi Jnum | J:261624 | Mgi Id | MGI:6155931 |
| Doi | 10.1128/MCB.00452-17 | Citation | Kim GD, et al. (2017) CITED2 restrains pro-inflammatory macrophage activation and response. Mol Cell Biol |
| abstractText | Macrophages are strategically distributed in mammalian tissues and play an essential role in priming immune response. However, macrophages need to constantly strike a balance between activation and inhibition state to avoid a futile inflammatory reaction. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage pro-inflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPARgamma) activation and attendant select anti-inflammatory gene expression in macrophages. More importantly, deficiency of CITED2 resulted in significant attenuation in rosiglitazone-induced PPARgamma activity, PPARgamma recruitment to target gene promoters and anti-inflammatory target gene expression in macrophages. Interestingly, deficiency of Cited2 strikingly heightened pro-inflammatory gene expression through stabilization of hypoxia-inducible factor 1 alpha (HIF1alpha) protein in macrophages. Further, overexpression of Egln3 or inhibition of HIF1alpha in Cited2-deficient macrophages completely reversed elevated pro-inflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid-specific deletion of Cited2 were highly susceptible to endotoxin-induced sepsis symptomatology and mortality. Collectively, our observations identify CITED2 as a novel negative regulator of macrophage pro-inflammatory activation and protect the host from inflammatory insults. |
