| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B, Activator Protein-1, c-Jun N-Terminal Protein Kinase, and Apoptosis1
Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
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-
B activation by suppressing I-B
(inhibitory subunit of
NF-B) degradation. We in this study show that leflunomide also
blocks NF-B reporter gene expression induced by TNFR1,
TNFR-associated factor 2, and NF-B-inducing kinase (NIK), but not
that activated by the p65 subunit of NF-B, suggesting that
leflunomide acts downstream of NIK. Leflunomide suppressed TNF-induced
phosphorylation of I-B, as well as activation of I-B
kinase-
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.
This article has been cited by other articles:
|
|
 |
|
  J. Gardiner, D. Barton, J. May Vanslambrouck, F. Braet, D. Hall, J. Marc, and R. Overall Defects in Tongue Papillae and Taste Sensation Indicate a Problem with Neurotrophic Support in Various Neurological Diseases Neuroscientist, June 1, 2008; 14(3): 240 - 250. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Leca, K. A. Muczynski, J. A. Jefferson, I. H. de Boer, J. Kowalewska, E. A. Kendrick, R. Pichler, and C. L. Davis Higher Levels of Leflunomide Are Associated with Hemolysis and Are not Superior to Lower Levels for BK Virus Clearance in Renal Transplant Patients Clin. J. Am. Soc. Nephrol., May 1, 2008; 3(3): 829 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bhardwaj, G. Sethi, S. Vadhan-Raj,, C. Bueso-Ramos, Y. Takada, U. Gaur, A. S. Nair, S. Shishodia, and B. B. Aggarwal Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-{kappa}B-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells Blood, March 15, 2007; 109(6): 2293 - 2302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. F. Si, J. Li, X. W. Lu, and Y. Jin Suppressive Effects of Leflunomide on Leptin-Induced Collagen I Production Involved in Hepatic Stellate Cell Proliferation Experimental Biology and Medicine, March 1, 2007; 232(3): 427 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Agrawal and A Sharma Dual mycobacterial infection in the setting of leflunomide treatment for rheumatoid arthritis Ann Rheum Dis, February 1, 2007; 66(2): 277 - 277. [Full Text] [PDF]
|
|
|
|
|
|
M Cutolo, S Capellino, P Montagna, A Sulli, B Seriolo, and B Villaggio Anti-inflammatory effects of leflunomide in combination with methotrexate on co-culture of T lymphocytes and synovial macrophages from rheumatoid arthritis patients Ann Rheum Dis, June 1, 2006; 65(6): 728 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hocevar, B. Rozman, S. Praprotnik, B. Lestan, D. Erzen, V. Petric, and M. Tomsic Leflunomide-associated tuberculosis? Rheumatology, February 1, 2006; 45(2): 228 - 229. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Doan and E. Massarotti Rheumatoid Arthritis: An Overview of New and Emerging Therapies J. Clin. Pharmacol., July 1, 2005; 45(7): 751 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Stuhlmeier Effects of Leflunomide on Hyaluronan Synthases (HAS): NF-{kappa}B-Independent Suppression of IL-1-Induced HAS1 Transcription by Leflunomide J. Immunol., June 1, 2005; 174(11): 7376 - 7382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Akiho, P. Lovato, Y. Deng, P. J. M. Ceponis, P. Blennerhassett, and S. M. Collins Interleukin-4- and -13-induced hypercontractility of human intestinal muscle cells-implication for motility changes in Crohn's disease Am J Physiol Gastrointest Liver Physiol, April 1, 2005; 288(4): G609 - G615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Migita, T. Miyashita, Y. Maeda, M. Nakamura, H. Yatsuhashi, H. Ishibashi, and K. Eguchi An active metabolite of leflunomide, A77 1726, inhibits the production of serum amyloid A protein in human hepatocytes Rheumatology, April 1, 2005; 44(4): 443 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D Gensburger, M Kawashima, H Marotte, J Kanitakis, and P Miossec Lupus erythematosus with leflunomide: induction or reactivation? Ann Rheum Dis, January 1, 2005; 64(1): 153 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Grisar, M Aringer, M D Koller, G H Stummvoll, D Eselbock, B Zwolfer, C W Steiner, B Zierhut, L Wagner, P Pietschmann, et al. Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells Ann Rheum Dis, December 1, 2004; 63(12): 1632 - 1637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Korn, T. Magnus, K. Toyka, and S. Jung Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide-- mechanisms independent of pyrimidine depletion J. Leukoc. Biol., November 1, 2004; 76(5): 950 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Aggarwal, Y. Takada, A. M. Mhashilkar, K. Sieger, S. Chada, and B. B. Aggarwal Melanoma Differentiation-Associated Gene-7/IL-24 Gene Enhances NF-{kappa}B Activation and Suppresses Apoptosis Induced by TNF J. Immunol., October 1, 2004; 173(7): 4368 - 4376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M C Kraan, T J M Smeets, M J van Loon, F C Breedveld, B A C Dijkmans, and P P Tak Differential effects of leflunomide and methotrexate on cytokine production in rheumatoid arthritis Ann Rheum Dis, September 1, 2004; 63(9): 1056 - 1061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Olsen and C. M. Stein New Drugs for Rheumatoid Arthritis N. Engl. J. Med., May 20, 2004; 350(21): 2167 - 2179. [Full Text] [PDF]
|
|
|
|
|
|
A. C. Bharti, Y. Takada, and B. B. Aggarwal Curcumin (Diferuloylmethane) Inhibits Receptor Activator of NF-{kappa}B Ligand-Induced NF-{kappa}B Activation in Osteoclast Precursors and Suppresses Osteoclastogenesis J. Immunol., May 15, 2004; 172(10): 5940 - 5947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J van der Heijden, M C de Jong, B A C Dijkmans, W F Lems, R Oerlemans, I Kathmann, G L Scheffer, R J Scheper, Y G Assaraf, and G Jansen Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs Ann Rheum Dis, February 1, 2004; 63(2): 131 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Quemeneur, L.-M. Gerland, M. Flacher, M. Ffrench, J.-P. Revillard, and L. Genestier Differential Control of Cell Cycle, Proliferation, and Survival of Primary T Lymphocytes by Purine and Pyrimidine Nucleotides J. Immunol., May 15, 2003; 170(10): 4986 - 4995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Cutolo, A Sulli, P Ghiorzo, C Pizzorni, C Craviotto, and B Villaggio Anti-inflammatory effects of leflunomide on cultured synovial macrophages from patients with rheumatoid arthritis Ann Rheum Dis, April 1, 2003; 62(4): 297 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Bharti, N. Donato, S. Singh, and B. B. Aggarwal Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and Ikappa Balpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis Blood, February 1, 2003; 101(3): 1053 - 1062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Burger, N. Begue-Pastor, S. Benavent, L. Gruaz, M.-T. Kaufmann, R. Chicheportiche, and J.-M. Dayer The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E2, matrix metalloproteinase 1 and interleukin 6 in human fibroblast-like synoviocytes Rheumatology, January 1, 2003; 42(1): 89 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Dimitrova, A. Skapenko, M. L. Herrmann, R. Schleyerbach, J. R. Kalden, and H. Schulze-Koops Restriction of De Novo Pyrimidine Biosynthesis Inhibits Th1 Cell Activation and Promotes Th2 Cell Differentiation J. Immunol., September 15, 2002; 169(6): 3392 - 3399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Majumdar, B. Lamothe, and B. B. Aggarwal Thalidomide Suppresses NF-{kappa}B Activation Induced by TNF and H2O2, But Not That Activated by Ceramide, Lipopolysaccharides, or Phorbol Ester J. Immunol., March 15, 2002; 168(6): 2644 - 2651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yu, K. E. Pinkerton, and H. Witschi Short-Term Exposure to Aged and Diluted Sidestream Cigarette Smoke Enhances Ozone-Induced Lung Injury in B6C3F1 Mice Toxicol. Sci., January 1, 2002; 65(1): 99 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Majumdar and B. B. Aggarwal Methotrexate Suppresses NF-{kappa}B Activation Through Inhibition of I{kappa}B{alpha} Phosphorylation and Degradation J. Immunol., September 1, 2001; 167(5): 2911 - 2920. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
