Other
13 Authors
- Deng CX,
- Bertola A,
- Xu X,
- Reynolds D,
- Maruyama T,
- Xiao C,
- Lahusen TJ,
- Young HA,
- Chen Q,
- Chen WJ,
- Wang RH,
- Gao B,
- Park O
| First Author | Xiao C | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 50 | Pages | 41903-13 |
| PubMed ID | 23076146 | Mgi Jnum | J:193418 |
| Mgi Id | MGI:5468388 | Doi | 10.1074/jbc.M112.415182 |
| Citation | Xiao C, et al. (2012) Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice. J Biol Chem 287(50):41903-13 |
| abstractText | The human body has a remarkable ability to regulate inflammation, a biophysical response triggered by virus infection and tissue damage. Sirt6 is critical for metabolism and lifespan; however, its role in inflammation is unknown. Here we show that Sirt6-null (Sirt6(-/-)) mice developed chronic liver inflammation starting at approximately 2 months of age, and all animals were affected by 7-8 months of age. Deletion of Sirt6 in T cells or myeloid-derived cells was sufficient to induce liver inflammation and fibrosis, albeit to a lesser degree than that in the global Sirt6(-/-) mice, suggesting that Sirt6 deficiency in the immune cells is the cause. Consistently, macrophages derived from the bone marrow of Sirt6(-/-) mice showed increased MCP-1, IL-6, and TNFalpha expression levels and were hypersensitive to LPS stimulation. Mechanistically, SIRT6 interacts with c-JUN and deacetylates histone H3 lysine 9 (H3K9) at the promoter of proinflammatory genes whose expression involves the c-JUN signaling pathway. Sirt6-deficient macrophages displayed hyperacetylation of H3K9 and increased occupancy of c-JUN in the promoter of these genes, leading to their elevated expression. These data suggest that Sirt6 plays an anti-inflammatory role in mice by inhibiting c-JUN-dependent expression of proinflammatory genes. |
