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Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression.
J Immunol. 1999 Feb 15; 162(4):2095-102.JI

Abstract

Leflunomide is a novel immunosuppressive and antiinflammatory agent currently being tested for treatment of autoimmune diseases and transplant rejection. NF-kappa B is a transcription factor activated in response to a wide variety of inflammatory stimuli, including TNF, but whether leflunomide blocks NF-kappa B activation is not known. In the present report we demonstrate that treatment of a human T cell line (Jurkat) with leflunomide blocks TNF-mediated NF-kappa B activation in a dose- and time-dependent manner, with maximum inhibition at 5-10 microM. Inhibition was not restricted to TNF-induced activation, because leflunomide also inhibited NF-kappa B activation induced by other inflammatory agents, including phorbol ester, LPS, H2O2, okadaic acid, and ceramide. Leflunomide blocked the degradation of I kappa B alpha and subsequent nuclear translocation of the p65 subunit, steps essential for NF-kappa B activation. This correlated with inhibition of dual specificity-mitogen-activated protein kinase kinase as well as an Src protein tyrosine kinase, p56lck, by leflunomide. Reducing agents did not reverse the effect of leflunomide. Leflunomide also suppressed the TNF-activated NF-kappa B-dependent reporter gene expression. Our results thus indicate that leflunomide is a potent inhibitor of NF-kappa B activation induced by a wide variety of inflammatory stimuli, and this provides the molecular basis for its anti-inflammatory and immunosuppressive effects.

Authors+Show Affiliations

Cytokine Research Laboratory, Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9973483

Citation

Manna, S K., and B B. Aggarwal. "Immunosuppressive Leflunomide Metabolite (A77 1726) Blocks TNF-dependent Nuclear Factor-kappa B Activation and Gene Expression." Journal of Immunology (Baltimore, Md. : 1950), vol. 162, no. 4, 1999, pp. 2095-102.
Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol. 1999;162(4):2095-102.
Manna, S. K., & Aggarwal, B. B. (1999). Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. Journal of Immunology (Baltimore, Md. : 1950), 162(4), 2095-102.
Manna SK, Aggarwal BB. Immunosuppressive Leflunomide Metabolite (A77 1726) Blocks TNF-dependent Nuclear Factor-kappa B Activation and Gene Expression. J Immunol. 1999 Feb 15;162(4):2095-102. PubMed PMID: 9973483.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. AU - Manna,S K, AU - Aggarwal,B B, PY - 1999/2/11/pubmed PY - 1999/2/11/medline PY - 1999/2/11/entrez SP - 2095 EP - 102 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 162 IS - 4 N2 - Leflunomide is a novel immunosuppressive and antiinflammatory agent currently being tested for treatment of autoimmune diseases and transplant rejection. NF-kappa B is a transcription factor activated in response to a wide variety of inflammatory stimuli, including TNF, but whether leflunomide blocks NF-kappa B activation is not known. In the present report we demonstrate that treatment of a human T cell line (Jurkat) with leflunomide blocks TNF-mediated NF-kappa B activation in a dose- and time-dependent manner, with maximum inhibition at 5-10 microM. Inhibition was not restricted to TNF-induced activation, because leflunomide also inhibited NF-kappa B activation induced by other inflammatory agents, including phorbol ester, LPS, H2O2, okadaic acid, and ceramide. Leflunomide blocked the degradation of I kappa B alpha and subsequent nuclear translocation of the p65 subunit, steps essential for NF-kappa B activation. This correlated with inhibition of dual specificity-mitogen-activated protein kinase kinase as well as an Src protein tyrosine kinase, p56lck, by leflunomide. Reducing agents did not reverse the effect of leflunomide. Leflunomide also suppressed the TNF-activated NF-kappa B-dependent reporter gene expression. Our results thus indicate that leflunomide is a potent inhibitor of NF-kappa B activation induced by a wide variety of inflammatory stimuli, and this provides the molecular basis for its anti-inflammatory and immunosuppressive effects. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/9973483/Immunosuppressive_leflunomide_metabolite__A77_1726__blocks_TNF_dependent_nuclear_factor_kappa_B_activation_and_gene_expression_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=9973483 DB - PRIME DP - Unbound Medicine ER -