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In this study, we show that nonactivated macrophages express basal levels of mTNF-\u03b1 and respond to anti\u2013TNF-\u03b1 Abs by triggering the MAPK kinase 4 signaling pathway. The pathway induces TGF-\u03b2. Based on inhibitory experiments, the production of TGF-\u03b21 is regulated via Jun kinases, whereas that of other TGF-\u03b2s is regulated via p38 MAPKs. Exposure to LPS further induced the expression of mTNF-\u03b1, and triggering of mTNF-\u03b1 strongly suppressed the LPS-induced proinflammatory response. Neutralizing TGF-\u03b2 by Abs prevented the mTNF-\u03b1\u2013mediated suppression of LPS-induced proinflammatory cytokine formation, indicating that the immune-suppressive effect of mTNF-\u03b1 is mediated via TGF-\u03b2. Although apoptotic cells are also known to suppress LPS-induced proinflammatory cytokine formation in macrophages by upregulating TGF-\u03b2, we show that they do not use the mTNF-\u03b1 signaling pathway. Because TGF-\u03b2 possesses a wide range of immune-suppressive effects, our data indicate that upregulation of TGF-\u03b2 synthesis by those TNF-\u03b1\u2013targeting molecules, which are able to trigger mTNF-\u03b1, might contribute to their therapeutic effect in the treatment of certain inflammatory diseases such as Crohn\u2019s disease, Wegener\u2019s granulomatosis, or sarcoidosis. Additionally, none of the TNF-\u03b1\u2013targeting molecules is expected to interfere with the immune-silencing effects of apoptotic cells.<\/jats:p>","DOI":"10.4049\/jimmunol.1501573","type":"journal-article","created":{"date-parts":[[2016,1,5]],"date-time":"2016-01-05T01:49:04Z","timestamp":1451958544000},"page":"1146-1157","source":"Crossref","is-referenced-by-count":42,"title":["Transmembrane TNF-\u03b1 Reverse Signaling Inhibits Lipopolysaccharide-Induced Proinflammatory Cytokine Formation in Macrophages by Inducing TGF-\u03b2: Therapeutic Implications"],"prefix":"10.1093","volume":"196","author":[{"given":"Anna","family":"Pallai","sequence":"first","affiliation":[{"name":"Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen , H-4012 Debrecen ,","place":["Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Be\u00e1ta","family":"Kiss","sequence":"additional","affiliation":[{"name":"Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen , H-4012 Debrecen ,","place":["Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy","family":"Vereb","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Research Center of Molecular Medicine, University of Debrecen , H-4012 Debrecen ,","place":["Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0985-9076","authenticated-orcid":false,"given":"Marietta","family":"Armaka","sequence":"additional","affiliation":[{"name":"Division of Immunology, Biomedical Sciences Research Center Alexander Fleming , 16672 Vari ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Kollias","sequence":"additional","affiliation":[{"name":"Division of Immunology, Biomedical Sciences Research Center Alexander Fleming , 16672 Vari ,","place":["Greece"]},{"name":"Department of Physiology, School of Medicine, National and Kapodistrian University of Athens , 15771 Athens ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7794-6844","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Szekanecz","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, University of Debrecen , H-4012 Debrecen ,","place":["Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsa","family":"Szondy","sequence":"additional","affiliation":[{"name":"Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen , H-4012 Debrecen ,","place":["Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,2,1]]},"reference":[{"key":"2025030702123068700_r1","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nri1184","article-title":"Signalling pathways of the TNF superfamily: a double-edged sword","volume":"3","author":"Aggarwal","year":"2003","journal-title":"Nat. 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