| First Author | Kandel-Kfir M | Year | 2020 |
| Journal | Mol Immunol | Volume | 117 |
| Pages | 101-109 | PubMed ID | 31759325 |
| Mgi Jnum | J:292490 | Mgi Id | MGI:6436044 |
| Doi | 10.1016/j.molimm.2019.11.004 | Citation | Kandel-Kfir M, et al. (2020) IFNgamma potentiates TNFalpha/TNFR1 signaling to induce FAT10 expression in macrophages. Mol Immunol 117:101-109 |
| abstractText | INTRODUCTION: The tight regulation of the cytokine network during macrophage activation is of prime importance to enable a fast and potent innate immune response against exogenous pathogens. The inflammation mediating ubiquitin-like protein HLA-F adjacent transcript number 10 (FAT10) was shown to be transcriptionally regulated by and also regulate the nuclear factor-kappaB (NFkappaB) signaling pathway. However, very little is known about the regulation of FAT10 gene expression during macrophage activation. RESULTS: RNA sequencing of interferon (IFN)gamma-stimulated mouse peritoneal macrophages analyzed by ingenuity pathway analysis revealed significant involvement of tumor necrosis factor receptor 1 (TNFR1) signaling in addition to IFNgamma signaling. Subsequently, IFNgamma robustly upregulated FAT10 expression compared to a milder induction seen with TNFalpha or lipopolysaccharide (LPS) stimulation. While low dose IFNgamma with TNFalpha synergistically elevated FAT10 expression, preincubation of macrophages with IFNgamma strongly augmented TNFalpha-induced FAT10 expression. Moreover, a short preincubation with IFNgamma, which did not elevate FAT10, was sufficient to potentiate the induction of FAT10 by TNFalpha. A double augmentation mechanism of TNFalpha signaling was demonstrated, where IFNgamma rapidly induced the expression of TNFalpha and TNFR1, which further augmented the induction of TNFalpha and TNFR1 expression by TNFalpha. Importantly, the induction of FAT10 by IFNgamma in macrophages from TNFalpha-deficient or TNFR1-deficient mice was completely inhibited compared to macrophages from wild type (WT) mice. Finally, we show that TNFalpha-induced FAT10 expression is dependent on NFkappaB signaling. CONCLUSION: IFNgamma potentiates the TNFalpha/TNFR1 signaling pathway to induce FAT10 expression in mouse macrophages, mediated through NFkappaB network. |
