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Thalidomide suppresses NF-kappa B activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester.
J Immunol. 2002 Mar 15; 168(6):2644-51.JI

Abstract

Thalidomide ([+]-alpha-phthalimidoglutarimide), a psychoactive drug that readily crosses the blood-brain barrier, has been shown to exhibit anti-inflammatory, antiangiogenic, and immunosuppressive properties through a mechanism that is not fully established. Due to the central role of NF-kappaB in these responses, we postulated that thalidomide mediates its effects through suppression of NF-kappaB activation. We investigated the effects of thalidomide on NF-kappaB activation induced by various inflammatory agents in Jurkat cells. The treatment of these cells with thalidomide suppressed TNF-induced NF-kappaB activation, with optimum effect occurring at 50 microg/ml thalidomide. These effects were not restricted to T cells, as other hematopoietic and epithelial cell types were also inhibited. Thalidomide suppressed H(2)O(2)-induced NF-kappaB activation but had no effect on NF-kappaB activation induced by PMA, LPS, okadaic acid, or ceramide, suggesting selectivity in suppression of NF-kappaB. The suppression of TNF-induced NF-kappaB activation by thalidomide correlated with partial inhibition of TNF-induced degradation of an inhibitory subunit of NF-kappaB (IkappaBalpha), abrogation of IkappaBalpha kinase activation, and inhibition of NF-kappaB-dependent reporter gene expression. Thalidomide abolished the NF-kappaB-dependent reporter gene expression activated by overexpression of TNFR1, TNFR-associated factor-2, and NF-kappaB-inducing kinase, but not that activated by the p65 subunit of NF-kappaB. Overall, our results clearly demonstrate that thalidomide suppresses NF-kappaB activation specifically induced by TNF and H(2)O(2) and that this may contribute to its role in suppression of proliferation, inflammation, angiogenesis, and the immune system.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

11884428

Citation

Majumdar, Sekhar, et al. "Thalidomide Suppresses NF-kappa B Activation Induced By TNF and H2O2, but Not That Activated By Ceramide, Lipopolysaccharides, or Phorbol Ester." Journal of Immunology (Baltimore, Md. : 1950), vol. 168, no. 6, 2002, pp. 2644-51.
Majumdar S, Lamothe B, Aggarwal BB. Thalidomide suppresses NF-kappa B activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester. J Immunol. 2002;168(6):2644-51.
Majumdar, S., Lamothe, B., & Aggarwal, B. B. (2002). Thalidomide suppresses NF-kappa B activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester. Journal of Immunology (Baltimore, Md. : 1950), 168(6), 2644-51.
Majumdar S, Lamothe B, Aggarwal BB. Thalidomide Suppresses NF-kappa B Activation Induced By TNF and H2O2, but Not That Activated By Ceramide, Lipopolysaccharides, or Phorbol Ester. J Immunol. 2002 Mar 15;168(6):2644-51. PubMed PMID: 11884428.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thalidomide suppresses NF-kappa B activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester. AU - Majumdar,Sekhar, AU - Lamothe,Betty, AU - Aggarwal,Bharat B, PY - 2002/3/9/pubmed PY - 2002/4/16/medline PY - 2002/3/9/entrez SP - 2644 EP - 51 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 168 IS - 6 N2 - Thalidomide ([+]-alpha-phthalimidoglutarimide), a psychoactive drug that readily crosses the blood-brain barrier, has been shown to exhibit anti-inflammatory, antiangiogenic, and immunosuppressive properties through a mechanism that is not fully established. Due to the central role of NF-kappaB in these responses, we postulated that thalidomide mediates its effects through suppression of NF-kappaB activation. We investigated the effects of thalidomide on NF-kappaB activation induced by various inflammatory agents in Jurkat cells. The treatment of these cells with thalidomide suppressed TNF-induced NF-kappaB activation, with optimum effect occurring at 50 microg/ml thalidomide. These effects were not restricted to T cells, as other hematopoietic and epithelial cell types were also inhibited. Thalidomide suppressed H(2)O(2)-induced NF-kappaB activation but had no effect on NF-kappaB activation induced by PMA, LPS, okadaic acid, or ceramide, suggesting selectivity in suppression of NF-kappaB. The suppression of TNF-induced NF-kappaB activation by thalidomide correlated with partial inhibition of TNF-induced degradation of an inhibitory subunit of NF-kappaB (IkappaBalpha), abrogation of IkappaBalpha kinase activation, and inhibition of NF-kappaB-dependent reporter gene expression. Thalidomide abolished the NF-kappaB-dependent reporter gene expression activated by overexpression of TNFR1, TNFR-associated factor-2, and NF-kappaB-inducing kinase, but not that activated by the p65 subunit of NF-kappaB. Overall, our results clearly demonstrate that thalidomide suppresses NF-kappaB activation specifically induced by TNF and H(2)O(2) and that this may contribute to its role in suppression of proliferation, inflammation, angiogenesis, and the immune system. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/11884428/Thalidomide_suppresses_NF_kappa_B_activation_induced_by_TNF_and_H2O2_but_not_that_activated_by_ceramide_lipopolysaccharides_or_phorbol_ester_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=11884428 DB - PRIME DP - Unbound Medicine ER -