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
Nutrition
Medicine
Geneeskunde
Pharmacology
Toxicology
Caspase 8
Salazosulfapyridine
Tumor necrosis factor alpha
Animal cell
Antiinflammatory activity
Apoptosis
Crohn disease
Cytokine production
Drug mechanism
Macrophage
Mouse
Nonhuman
Priority journal
Protein expression
Rheumatoid arthritis
Adenosine
Animals
Anti-Inflammatory Agents, Non-Steroidal
Apoptosis
Caspases
Cells, Cultured
Cysteine Proteinase Inhibitors
Humans
Macrophage Activation
Macrophages
Macrophages, Peritoneal
Methotrexate
Mice
Mice, Inbred C57BL
Sulfasalazine
Tumor Necrosis Fac
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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