Necroptosis, a form of programmed lytic cell death, has emerged as a driving factor in the pathogenesis of acute lung injury. One specific inflammatory mediator that is of interest is interferon-γ (IFN-γ). Our laboratory has reported that IFN-γ is the most potent enhancer of necroptosis in primary lung epithelial cells and macrophages by upregulating MLKL expression. How IFN-γ enhances necroptosis and MLKL upregulation is currently unknown. In this research, we utilized multiple approaches to study the potential molecular mechanisms of IFN-γ promoted necroptosis in macrophages. We found that MLKL and ZBP1 are significantly upregulated by IFN-γ through an unknown pathway downstream of Jak kinase. The phosphorylation of RIPK1, RIPK3, and MLKL was accelerated by pretreatment with IFN-γ upon induction of necroptosis. Whereas IFN-γ did not affect the ubiquitination of MLKL. Moreover, we found that necroptosis caused MLKL degradation or loss in the membrane fraction, which was prevented by IFN-γ treatment. This effect may be a critical mechanism responsible for the enhanced necroptosis observed in IFN-γ pretreated macrophages.

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Dr. Hua Tang, Dr. Pierre Neuenschwander, Dr. Guohua Yi, Dr. Guoqing Qian, Dr. Ali Azghani


Master of Science in Biotechnology

Available for download on Wednesday, August 06, 2025