| Leflunomide suppresses TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis. | |
| | |
MedLine Citation:
|
PMID: 11067959 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Leflunomide is a pyrimidine biosynthesis inhibitor that has recently been approved for treatment of rheumatoid arthritis. However, the mechanism of leflunomide's antiarthritis activity and is not fully understood. The critical role that TNF plays in rheumatoid arthritis led us to postulate that leflunomide blocks TNF signaling. Previously, we have demonstrated that leflunomide inhibits TNF-induced NF-kappaB activation by suppressing I-kappaBalpha (inhibitory subunit of NF-kappaB) degradation. We in this study show that leflunomide also blocks NF-kappaB reporter gene expression induced by TNFR1, TNFR-associated factor 2, and NF-kappaB-inducing kinase (NIK), but not that activated by the p65 subunit of NF-kappaB, suggesting that leflunomide acts downstream of NIK. Leflunomide suppressed TNF-induced phosphorylation of I-kappaBalpha, as well as activation of I-kappaBalpha kinase-beta located downstream to NIK. Leflunomide also inhibited TNF-induced activation of AP-1 and the c-Jun N-terminal protein kinase activation. TNF-mediated cytotoxicity and caspase-induced poly(ADP-ribose) polymerase cleavage were also completely abrogated by treatment of Jurkat T cells with leflunomide. Leflunomide suppressed TNF-induced reactive oxygen intermediate generation and lipid peroxidation, which may explain most of its effects on TNF signaling. The suppressive effects of leflunomide on TNF signaling were completely reversible by uridine, indicating a critical role for pyrimidine biosynthesis in TNF-mediated cellular responses. Overall, our results suggest that suppression of TNF signaling is one of the possible mechanisms for inhibitory activity of leflunomide against rheumatoid arthritis. |
| | |
Authors:
|
S K Manna; A Mukhopadhyay; B B Aggarwal |
Related Documents
:
|
16717119 - Ifngamma-dependent, spontaneous development of colorectal carcinomas in socs1-deficient... 17909069 - Smad7 sensitizes tumor necrosis factor induced apoptosis through the inhibition of anti... 10720949 - Overexpression of truncated i kappa b alpha potentiates tnf-alpha-induced apoptosis in ... 14625479 - Pyrrolidine dithiocarbamate reduces the severity of cerulein-induced murine acute pancr... 11572859 - Butyrate suppression of colonocyte nf-kappa b activation and cellular proteasome activity. 10614719 - Antioxidants attenuate nuclear factor-kappa b activation and tumor necrosis factor-alph... 11199709 - Effects of a bacterial cell wall fragment on monocyte inflammatory function. 11731469 - Overlapping functions of lysosomal acid phosphatase (lap) and tartrate-resistant acid p... 10535869 - Enhancing lamina propria th1 cell responses with interleukin 12 produces severe tissue ... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 165 ISSN: 0022-1767 ISO Abbreviation: J. Immunol. Publication Date: 2000 Nov |
Date Detail:
|
Created Date: 2000-11-21 Completed Date: 2000-12-22 Revised Date: 2009-11-19 |
Medline Journal Info:
|
Nlm Unique ID: 2985117R Medline TA: J Immunol Country: UNITED STATES |
Other Details:
|
Languages: eng Pagination: 5962-9 Citation Subset: AIM; IM |
Affiliation:
|
Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Apoptosis
/
drug effects* Caspases / antagonists & inhibitors, metabolism Cells, Cultured Cytotoxicity, Immunologic / drug effects DNA-Binding Proteins / antagonists & inhibitors, metabolism Enzyme Activation / drug effects, immunology Gene Expression Regulation / drug effects, immunology Genes, Reporter / immunology Growth Inhibitors / pharmacology* Hela Cells Humans I-kappa B Kinase I-kappa B Proteins* Immunosuppressive Agents / antagonists & inhibitors, pharmacology* Isoxazoles / antagonists & inhibitors, pharmacology* JNK Mitogen-Activated Protein Kinases Jurkat Cells Lipid Peroxidation / drug effects, immunology Mitogen-Activated Protein Kinases / antagonists & inhibitors*, metabolism NF-kappa B / antagonists & inhibitors*, biosynthesis, genetics, metabolism Phosphorylation Protein-Serine-Threonine Kinases / antagonists & inhibitors, metabolism Reactive Oxygen Species / immunology, metabolism Receptors, Tumor Necrosis Factor / metabolism Signal Transduction / drug effects, immunology Transcription Factor AP-1 / antagonists & inhibitors*, metabolism Tumor Necrosis Factor-alpha / antagonists & inhibitors, physiology* Uridine / pharmacology |
| Chemical | |
Reg. No./Substance:
|
0/DNA-Binding Proteins; 0/Growth Inhibitors; 0/I-kappa B Proteins; 0/Immunosuppressive Agents; 0/Isoxazoles; 0/NF-kappa B; 0/Reactive Oxygen Species; 0/Receptors, Tumor Necrosis Factor; 0/Transcription Factor AP-1; 0/Tumor Necrosis Factor-alpha; 139874-52-5/NF-kappaB inhibitor alpha; 58-96-8/Uridine; 75706-12-6/leflunomide; EC 2.7.1.-/IKBKE protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.10/CHUK protein, human; EC 2.7.11.10/I-kappa B Kinase; EC 2.7.11.10/IKBKB protein, human; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Triggering Fc alpha-receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antib...
Next Document: Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus.