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However, excessive or dysregulated NET formation is implicated in the pathogenesis of various conditions, including thrombosis, autoimmune diseases, and cancer. Despite their clinical significance, the specific intracellular signaling pathways underlying NET formation in response to proinflammatory cytokines, including tumor necrosis factor-\u03b1 (TNF-\u03b1), remain incompletely defined. Thus, in the present study, we aimed to elucidate the mechanisms underlying TNF-\u03b1-induced NET formation in human neutrophil-like differentiated HL-60 (dHL-60) cells. TNF-\u03b1 induced rapid, non-lytic NET formation in dHL-60 cells without compromising cell viability. Mechanistically, TNF-\u03b1 activated a signaling cascade involving c-Raf, MEK1\/2, and p38 mitogen-activated protein kinase (MAPK). This signaling cascade regulated the sequential caspase activation, with caspase-2 acting upstream of caspase-1 cleavage to promote NET formation. Collectively, these findings suggest that TNF-\u03b1 induces non-lytic NET formation via a defined c-Raf\u2013MEK1\/2\u2013p38 MAPK\u2013caspase pathway and a distinct caspase hierarchy. This mechanism offers a valuable experimental model for studying NET-mediated pathologies in proinflammatory environments.<\/jats:p>","DOI":"10.1177\/10799907261473767","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T10:43:54Z","timestamp":1786099434000},"page":"305-317","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["A Distinct c-Raf\u2013MEK1\/2\u2013p38 MAPK\u2013Caspase Signaling Pathway Mediates TNF-\u03b1-Induced Rapid and Non-Lytic Neutrophil Extracellular Trap Formation in Human Neutrophil-Like Cells"],"prefix":"10.1177","volume":"46","author":[{"given":"Sung-Hun","family":"Woo","sequence":"first","affiliation":[{"name":"Department of Biomedical Laboratory Science, Korea Nazarene University, Cheonan, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yerang","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, College of Health Science, Yonsei University, Wonju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, Korea Nazarene University, Cheonan, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0732-0122","authenticated-orcid":false,"given":"Byung Chul","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, College of Health Science, Yonsei University, Wonju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon Suk","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, College of Health Science, Yonsei University, Wonju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2001321"},{"key":"e_1_3_2_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1995.tb07099.x"},{"key":"e_1_3_2_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11121919"},{"key":"e_1_3_2_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1097-2765(03)00051-0"},{"key":"e_1_3_2_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2010.01037.x"},{"key":"e_1_3_2_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385"},{"key":"e_1_3_2_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2022.101595"},{"key":"e_1_3_2_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-025-01470-9"},{"key":"e_1_3_2_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2006.03261.x"},{"key":"e_1_3_2_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1703"},{"key":"e_1_3_2_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.06.025"},{"key":"e_1_3_2_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.496"},{"key":"e_1_3_2_14_1","doi-asserted-by":"publisher","DOI":"10.4103\/0366-6999.235122"},{"key":"e_1_3_2_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab329"},{"key":"e_1_3_2_16_1","doi-asserted-by":"publisher","DOI":"10.1055\/a-2609-3457"},{"key":"e_1_3_2_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2024.02.011"},{"key":"e_1_3_2_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam8897"},{"issue":"5","key":"e_1_3_2_19_1","first-page":"616","article-title":"Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential","volume":"12","author":"Jones JE","year":"2009","unstructured":"Jones JE, , Causey CP, , Knuckley B, et al. 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