Abstract
Interferon γ (IFN-γ) induces an inflammatory response and apoptotic cell death. Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with increased levels of inflammatory mediators, including tumour necrosis factor α (TNF-α) and T helper (Th) 17 cells, and downregulation of apoptosis of inflammatory cells. We hypothesized that IFN-γ would reduce inflammatory cell death in vitro and that loss of IFN-γ would aggravate inflammation in vivo. IFN-γ downregulated necroptosis and the expression of cellular FLICE-like inhibitory protein (cFLIPL) and mixed lineage kinase domain-like (MLKL). However, loss of IFN-γ promoted the production of cFLIPL and MLKL, and necroptosis. IFN-γ deficiency increased Th17 cell number and upregulated the expression of IL-17 and TNF-α. Expression of MLKL, receptor interacting protein kinase (RIPK)1, and RIPK3 was increased in the joints of mice with collagen-induced arthritis (CIA). Compared with wild-type mice with CIA, IFN-γ−/− CIA mice showed exacerbation of cartilage damage and joint inflammation, and acceleration of MLKL, RIPK1, and RIPK3 production in the joints. IFN-γ deficiency induced the activation of signal transducer and activator of transcription 3. These results suggest that IFN-γ regulates inflammatory cell death and may have potential for use in the treatment of RA.
Highlights
Necroptosis is defined as inflammatory cell death, which is a tightly programmed form of necrosis that can occur in a programmed manner under certain circumstances such as a massive inflammatory response[1, 2]
interferon γ (IFN-γ) significantly increased the percentage of propidium iodide (PI)-positive cells at 36 hours compared with WT mice
Because Mixed lineage kinase domain-like (MLKL) is a key marker of necroptosis related to RIPK1 activation[2] and TANK-binding kinase 1 (TBK1) can regulate cell survival[17], we measured MLKL expression in cells pretreated with necrostatin-1 or amlexanox
Summary
Necroptosis is defined as inflammatory cell death, which is a tightly programmed form of necrosis that can occur in a programmed manner under certain circumstances such as a massive inflammatory response[1, 2]. Cells undergo necroptosis rupture, which causes their contents to leak into the extracellular space This leakage caused by cell rupture differs from the processes caused by apoptosis and aggravates the inflammatory response[2, 3]. The pathogenesis of RA is complicated and involves cell death and the actions of proinflammatory cytokines. It is thought that deficient apoptosis in inflammatory cells may be involved in the pathogenesis of RA12. The cytokine interferon γ (IFN-γ) is involved in cell death and the inflammatory response. The level of p-MLKL is expressed as a relative ratio and t-MLKL was used to normalize the data. (C) Expression of PI and annexin V in splenocytes from WT and IFN-γ-knockout mice was induced by H2O2 and analysed by flow cytometry. (D) Expression of ROS in splenocytes from WT and IFN-γ-knockout mice was induced by H2O2 for 5 hours and analysed by flow cytometry
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