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Inflammatory cytokines like TNF often engage in interactions with other cytokines and growth factors, including TGF\u03b2, to orchestrate inflammatory process. Basal\/endogenous TGF\u03b2 signaling is a universal presence, yet the precise way TNF communicates with TGF\u03b2 signaling to regulate inflammation and influence inflammatory levels in macrophages has remained elusive. To address this question, this study utilized genetic approaches and a combination of molecular and cellular methods, including conditional TGF\u03b2 receptor knockout mice, human cells, RNAseq, ATACseq and Cut &amp; Run\u2010seq. The results reveal that the TGF\u03b2 signaling functions as a vital homeostatic pathway, curtailing uncontrolled inflammation in macrophages in response to TNF. Conversely, TNF employs two previously unrecognized mechanisms to suppress the TGF\u03b2 signaling. These mechanisms encompass epigenetic inhibition and RBP\u2010J\u2010mediated inhibition of the TGF\u03b2 signaling pathway by TNF. These mechanisms empower TNF to diminish the antagonistic influence exerted by the TGF\u03b2 signaling pathway, ultimately enhancing TNF's capacity to induce heightened levels of inflammation. This reciprocal suppression dynamic between TNF and the TGF\u03b2 signaling pathway holds unique physiopathological significance, as it serves as a crucial \u201cbraking\u201d mechanism. The balance between TNF levels and the activity of the endogenous TGF\u03b2 signaling pathway plays a pivotal role in determining the overall extent of inflammation. The potential for therapeutically augmenting the TGF\u03b2 signaling pathway presents an intriguing avenue for countering the impact of TNF and, consequently, developing innovative strategies for inflammation control.<\/jats:p>","DOI":"10.1096\/fj.202302230r","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T06:14:46Z","timestamp":1718604886000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Reciprocal suppression between\n                    <scp>TGF\u03b2<\/scp>\n                    signaling and\n                    <scp>TNF<\/scp>\n                    stimulation finetunes the macrophage inflammatory response"],"prefix":"10.1096","volume":"38","author":[{"given":"Yuhan","family":"Xia","sequence":"first","affiliation":[{"name":"Arthritis and Tissue Degeneration Program and David Z. 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