FOXO3 is involved in the tumor necrosis factor-driven inflammatory response in fibroblast-like synoviocytes

被引：23

作者：

Brandstetter, Bernhard ^{[1
]}

Dalwigk, Karolina ^{[1
]}

Platzer, Alexander ^{[1
]}

Niederreiter, Birgit ^{[1
]}

Kartnig, Felix ^{[2
]}

Fischer, Anita ^{[1
]}

Vladimer, Gregory, I ^{[2
]}

Byrne, Ruth A. ^{[1
]}

Sevelda, Florian ^{[3
]}

Holinka, Johannes ^{[3
]}

Pap, Thomas ^{[4
]}

Steiner, Gunter ^{[1
]}

Superti-Furga, Giulio ^{[2
,5
]}

Smolen, Josef S. ^{[1
]}

Kiener, Hans P. ^{[1
]}

Karonitsch, Thomas ^{[1
]}

机构：

[1] Med Univ Vienna, Div Rheumatol, Dept Med 3, A-1090 Vienna, Austria

[2] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria

[3] Med Univ Vienna, Dept Orthopaed, A-1090 Vienna, Austria

[4] Univ Hosp Muenster, Inst Musculoskeletal Med, D-48149 Munster, Germany

[5] Med Univ Vienna, Ctr Physiol & Pharmacol, A-1090 Vienna, Austria

来源：

LABORATORY INVESTIGATION | 2019年 / 99卷 / 05期

关键词：

RHEUMATOID-ARTHRITIS; SYNOVIAL FIBROBLASTS; EXPRESSION ANALYSIS; PI3K; INHIBITION; SUPPRESSES; NEUTROPHIL; ACTIVATION; PI3K-GAMMA; REGULATOR;

D O I：

10.1038/s41374-018-0184-7

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Forkhead box O 3 (FOXO3) perturbations in immune cells are increasingly linked to RA pathogenesis. Here, we show that FOXO3 is distinctly inactivated/phosphorylated in the FLS of rheumatoid synovitis. In vitro, stimulation of FLS with tumor necrosis factor-alpha alpha (TNF alpha) induced a rapid and sustained inactivation of FOXO3. mRNA profiling revealed that the inactivation of FOXO3 is important for the sustained pro-inflammatory interferon response to TNF alpha (CXCL9, CXCL10, CXCL11, and TNFSF18). Mechanistically, our studies demonstrate that the inactivation of FOXO3 results from TNF-induced downregulation of phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1). Thus, we identified FOXO3 and its modulator PIK3IP1 as a critical regulatory circuit for the inflammatory response of the resident mesenchymal cells to TNF alpha and contribute insight into how the synovial tissue brings about chronic inflammation that is driven by TNF alpha.

引用

页码：648 / 658

页数：11

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