Print Email Facebook Twitter The antiinflammatory drug sulfasalazine inhibits tumor necrosis factor alpha expression in macrophages by inducing apoptosis Title The antiinflammatory drug sulfasalazine inhibits tumor necrosis factor alpha expression in macrophages by inducing apoptosis Author Rodenburg, R.J.T. Ganga, A. van Lent, P.L.E.M. van de Putte, L.B.A. van Venrooij, W.J. Publication year 2000 Abstract Objective. Sulfasalazine (SSZ) is a commonly used drug in the treatment of inflammatory diseases such as rheumatoid arthritis and Crohn's disease. In both diseases, the proinflammatory cytokine tumor necrosis factor α (TNFα) plays a prominent role. In these studies, we investigated the mechanism by which SSZ inhibits TNFα expression in macrophages and macrophage-like cell lines. Methods. Monocyte-derived macrophages and several macrophage-like cell lines were exposed to SSZ in vitro, and the effect on TNFα expression was monitored by reverse transcriptase-polymerase chain reaction and Western blot analysis. In addition, the effects of SSZ in vivo were examined by intraperitoneally injecting mice with SSZ, after which peritoneal cells were harvested and examined using various staining methods. Results. Preincubation of macrophages with SSZ, but not with methotrexate, inhibited lipopolysaccharide (LPS)-induced TNFα expression. Inhibition of TNFα expression by SSZ coincided with the induction of apoptosis, as judged by the appearance of morphologic changes typical of apoptosis, such as nuclear condensation and fragmentation. Induction of apoptosis by SSZ was confirmed by TUNEL analysis and by the detection of cleaved U1-70K, a substrate of caspase 3. Intraperitoneal injections of SSZ in mice resulted in the induction of apoptosis of peritoneal cells within a few hours. SSZ-induced cleavage of the U1-70K protein was inhibited by Zn2+ and by specific inhibitors of caspases 3 and 8, but not caspases 1 and 9. Interestingly, the reduced expression of LPS-induced TNFα in the presence of SSZ was restored by inhibition of caspase 8. Conclusion. Inhibition of TNFα expression in macrophages by SSZ is due to the induction of apoptosis and involves the activation of caspase 8. Chemicals/CAS: Adenosine, 58-61-7; Anti-Inflammatory Agents, Non-Steroidal; Caspases, EC 3.4.22.-; Cysteine Proteinase Inhibitors; Methotrexate, 59-05-2; Sulfasalazine, 599-79-1; Tumor Necrosis Factor-alpha Subject NutritionMedicineGeneeskundePharmacologyToxicologyCaspase 8SalazosulfapyridineTumor necrosis factor alphaAnimal cellAntiinflammatory activityApoptosisCrohn diseaseCytokine productionDrug mechanismMacrophageMouseNonhumanPriority journalProtein expressionRheumatoid arthritisAdenosineAnimalsAnti-Inflammatory Agents, Non-SteroidalApoptosisCaspasesCells, CulturedCysteine Proteinase InhibitorsHumansMacrophage ActivationMacrophagesMacrophages, PeritonealMethotrexateMiceMice, Inbred C57BLSulfasalazineTumor Necrosis Fac To reference this document use: http://resolver.tudelft.nl/uuid:c587282e-c0eb-47d5-9ab6-4439c74dbb76 DOI https://doi.org/10.1002/1529-0131(200009)43:9<1941::aid-anr4>3.0.co;2-o TNO identifier 41672 ISSN 0004-3591 Source Arthritis & Rheumatism, 43 (9), 1941-1950 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.