{"doi":"10.3390/cells11030563","title":"Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL","abstract":"Necroptosis, a form of programmed lytic cell death, has emerged as a driving factor in the pathogenesis of acute lung injury (ALI). As ALI is often associated with a cytokine storm, we determined whether pro-inflammatory cytokines modulate the susceptibility of lung cells to necroptosis and which mediators dominate to control necroptosis. In this study, we pretreated/primed mouse primary lung epithelial and endothelial cells with various inflammatory mediators and assessed cell type-dependent responses to different necroptosis inducers and their underlying mechanisms. We found that interferon-γ (IFNγ) as low as 1 ng/mL preferentially promoted necroptosis and accelerated the release of damage-associated molecular patterns from primary alveolar and airway epithelial cells but not lung microvascular endothelial cells. Type-I IFNα was about fifty-fold less effective than IFNγ. Conversely, TNFα or agonists of Toll-like receptor-3 (TLR3), TLR4, TLR7 and TLR9 had a minor effect. The enhanced necroptosis in IFNγ-activated lung epithelial cells was dependent on IFNγ signaling and receptor-interacting protein kinase-3. We further showed that necroptosis effector mixed lineage kinase domain-like protein (MLKL) was predominantly induced by IFNγ, contributing to the enhanced necroptosis in lung epithelial cells. Collectively, our findings indicate that IFNγ is a potent enhancer of lung epithelial cell susceptibility to necroptosis.","journal":"Cells","year":2022,"id":244676,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":475861,"name":"Sreerama Shetty","orcid":null,"position":1,"is_corresponding":false},{"id":611110,"name":"Torry A. Tucker","orcid":"0000-0002-0823-3234","position":2,"is_corresponding":false},{"id":501233,"name":"Steven Idell","orcid":"0000-0003-4389-2152","position":3,"is_corresponding":false},{"id":501234,"name":"Hua Tang","orcid":"0000-0001-6886-7450","position":4,"is_corresponding":false},{"id":52592,"name":"Qin Hao","orcid":"0000-0002-6775-2181","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T00:23:30.364338Z","pmid":"35159372","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}