| First Author | Zheng S | Year | 2013 |
| Journal | Mol Cell Biol | Volume | 33 |
| Issue | 24 | Pages | 4857-71 |
| PubMed ID | 24100018 | Mgi Jnum | J:206079 |
| Mgi Id | MGI:5547867 | Doi | 10.1128/MCB.00797-13 |
| Citation | Zheng S, et al. (2013) NF-kappaB1 inhibits NOD2-induced cytokine secretion through ATF3-dependent mechanisms. Mol Cell Biol 33(24):4857-71 |
| abstractText | Regulation of microbially induced cytokine secretion is critical in intestinal immune homeostasis. NOD2, the Crohn's disease-associated bacterial peptidoglycan sensor, activates the NF-kappaB pathway. After chronic NOD2 stimulation in human macrophages, cytokine secretion is significantly attenuated, similar to the situation in the intestinal environment. We find that NF-kappaB1 (p105/p50) expression is upregulated with chronic NOD2 stimulation and is required for attenuation of cytokine secretion in vitro in human macrophages and in vivo in mice. Upon chronic NOD2 stimulation, regulation of both activating (H3K4Me2 and H4Ac) and inhibitory (H3K27Me3) histone modifications was observed within cytokine gene promoters; these outcomes were NF-kappaB1 dependent. In addition to enhanced binding to cytokine gene promoters with chronic NOD2 stimulation, NF-kappaB1 bound to the promoter of the transcriptional repressor, ATF3. ATF3 was then induced and bound to cytokine gene promoters; both features were impaired upon NF-kappaB1 knockdown. Restoring ATF3 expression under NF-kappaB1 knockdown conditions restored NOD2-mediated cytokine downregulation. Finally, NF-kappaB1 and ATF3 cooperate with other inhibitory pathways, including IRAKM and secreted mediators, to downregulate cytokine secretion after chronic NOD2 stimulation. Therefore, we identify NF-kappaB1 and ATF3 as critical mechanisms through which NOD2 downregulates cytokines and contributes to intestinal immune homeostasis. |
