| First Author | Hu B | Year | 2021 |
| Journal | Int Immunol | Volume | 33 |
| Issue | 9 | Pages | 461-468 |
| PubMed ID | 34423815 | Mgi Jnum | J:360681 |
| Mgi Id | MGI:7782678 | Doi | 10.1093/intimm/dxab029 |
| Citation | Hu B, et al. (2021) Ubiquitin-specific peptidase 18 negatively regulates and inhibits lipopolysaccharide-induced sepsis by targeting transforming growth factor-beta-activated kinase 1 activity. Int Immunol 33(9):461-468 |
| abstractText | Sepsis is an inflammatory disease with exacerbated inflammation at early stages. Inflammatory cytokines play critical roles in the pathophysiology of sepsis. Ubiquitin-specific peptidase 18 (USP18), a deubiquitinating enzyme, has been shown to modulate transforming growth factor-beta-activated kinase 1 (TAK1) activity. However, the precise role of USP18 in sepsis is not clear. Here, we investigated the potential effect of USP18 on inflammation in sepsis. We generated mice with USP18 or/and TAK1 deficiency in macrophages (USP18MKO mice, TAK1MKO mice and USP18MKO-TAK1MKO mice) and established a lipopolysaccharide (LPS)-induced sepsis model in mice. Bone marrow-derived macrophages were isolated from wild-type (WT), USP18MKO or TAK1MKO mice and treated with LPS or CpG, and the expression of cytokines including IL-6, IL-10, IL-1beta and tumor necrosis factor alpha (TNF-alpha) was measured. The activation of NF-kappaB, ERK and p38 signaling pathways and ubiquitination of TAK1 were detected. We induced sepsis in WT, USP18MKO, TAK1MKO or USP18MKO-TAK1MKO mice and evaluated the survival rate, lung pathology and inflammatory cytokine levels in serum. Macrophages deficient in USP18 produced significantly increased IL-6, IL-1beta and TNF-alpha post-LPS or -CpG stimulation. Macrophages deficient in USP18 had promoted activation of NF-kappaB, p38 and ERK, and increased ubiquitination of TAK1. Mice with TAK1 deficiency in macrophages had increased survival rates, decreased immune cell infiltration in lung and decreased pro-inflammatory cytokines in serum. In contrast, mice with USP18 deficiency in macrophages had decreased survival rates, increased cell infiltration in lung and increased pro-inflammatory cytokines in serum. USP18 alleviated LPS-induced sepsis by inhibiting TAK1 activity. |
