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Nepalolide A inhibits the expression of inducible nitric oxide synthase by modulating the degradation of IkappaB-alpha and IkappaB-beta in C6 glioma cells and rat primary astrocytes.
Br J Pharmacol 1999; 128(2):345-56BJ

Abstract

1 The effects of nepalolide A on the expression of inducible nitric oxide synthase (iNOS) caused by incubation with lipopolysaccharide/interferon-gamma (LPS/IFN-gamma) or tumour necrosis factor-alpha/interleukin-1beta/IFN-gamma (TNF-alpha/IL-1beta/IFN-gamma, mixed cytokines) in C6 glioma cells and primary astrocytes of rat were investigated. The mechanisms by which nepalolide A confers its effect on iNOS expression were also elucidated. 2 Treatment with LPS/IFN-gamma and mixed cytokines for 24 h elicited the induction of iNOS activity as determined by nitrite accumulation in the culture medium and assay of enzyme activity. Nepalolide A at 10 microM abrogated the LPS/IFN-gamma- and mixed cytokines-mediated induction of iNOS by more than 90% in C6 glioma cells, and by 80% for mixed cytokines-induced induction of iNOS in primary astrocytes. The effect of nepalolide A (2-10 microM) was concentration-dependent. 3 The inhibition of iNOS induction by nepalolide A was attributed to decreases in the content of iNOS protein and the level of iNOS mRNA, as measured by immunoblotting and reverse transcriptase-polymerase chain reaction. 4 Electrophoretic mobility shift assay was used to evaluate the effect of nepalolide A on the activation of nuclear factor-kappaB (NF-kappaB). Results showed that nepalolide A diminished the LPS/IFN-gamma-mediated association of NF-kappaB with consensus oligonucleotide in a concentration-dependent manner. The activation of NF-kappaB by mixed cytokines was modulated both in the extent of activation and in its time-course by nepalolide A. 5 The ability of nepalolide A to inhibit NF-kappaB activation was further confirmed by studies on the degradation of the inhibitor of NF-kappaB, IkappaB, as measured by immunoblotting. 6 The present study demonstrates that the attenuation of NF-kappaB activation by nepalolide A was mediated by blockade of the degradation of IkappaB, leading to suppression of the expression of iNOS.

Authors+Show Affiliations

National Research Institute of Chinese Medicine, NO. 155-1 SEC. 2, LiNung ST., Peitou, Taipei, Taiwan, Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

10510444

Citation

Wang, C N., et al. "Nepalolide a Inhibits the Expression of Inducible Nitric Oxide Synthase By Modulating the Degradation of IkappaB-alpha and IkappaB-beta in C6 Glioma Cells and Rat Primary Astrocytes." British Journal of Pharmacology, vol. 128, no. 2, 1999, pp. 345-56.
Wang CN, Shiao YJ, Lin YL, et al. Nepalolide A inhibits the expression of inducible nitric oxide synthase by modulating the degradation of IkappaB-alpha and IkappaB-beta in C6 glioma cells and rat primary astrocytes. Br J Pharmacol. 1999;128(2):345-56.
Wang, C. N., Shiao, Y. J., Lin, Y. L., & Chen, C. F. (1999). Nepalolide A inhibits the expression of inducible nitric oxide synthase by modulating the degradation of IkappaB-alpha and IkappaB-beta in C6 glioma cells and rat primary astrocytes. British Journal of Pharmacology, 128(2), pp. 345-56.
Wang CN, et al. Nepalolide a Inhibits the Expression of Inducible Nitric Oxide Synthase By Modulating the Degradation of IkappaB-alpha and IkappaB-beta in C6 Glioma Cells and Rat Primary Astrocytes. Br J Pharmacol. 1999;128(2):345-56. PubMed PMID: 10510444.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nepalolide A inhibits the expression of inducible nitric oxide synthase by modulating the degradation of IkappaB-alpha and IkappaB-beta in C6 glioma cells and rat primary astrocytes. AU - Wang,C N, AU - Shiao,Y J, AU - Lin,Y L, AU - Chen,C F, PY - 1999/10/8/pubmed PY - 1999/10/8/medline PY - 1999/10/8/entrez SP - 345 EP - 56 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 128 IS - 2 N2 - 1 The effects of nepalolide A on the expression of inducible nitric oxide synthase (iNOS) caused by incubation with lipopolysaccharide/interferon-gamma (LPS/IFN-gamma) or tumour necrosis factor-alpha/interleukin-1beta/IFN-gamma (TNF-alpha/IL-1beta/IFN-gamma, mixed cytokines) in C6 glioma cells and primary astrocytes of rat were investigated. The mechanisms by which nepalolide A confers its effect on iNOS expression were also elucidated. 2 Treatment with LPS/IFN-gamma and mixed cytokines for 24 h elicited the induction of iNOS activity as determined by nitrite accumulation in the culture medium and assay of enzyme activity. Nepalolide A at 10 microM abrogated the LPS/IFN-gamma- and mixed cytokines-mediated induction of iNOS by more than 90% in C6 glioma cells, and by 80% for mixed cytokines-induced induction of iNOS in primary astrocytes. The effect of nepalolide A (2-10 microM) was concentration-dependent. 3 The inhibition of iNOS induction by nepalolide A was attributed to decreases in the content of iNOS protein and the level of iNOS mRNA, as measured by immunoblotting and reverse transcriptase-polymerase chain reaction. 4 Electrophoretic mobility shift assay was used to evaluate the effect of nepalolide A on the activation of nuclear factor-kappaB (NF-kappaB). Results showed that nepalolide A diminished the LPS/IFN-gamma-mediated association of NF-kappaB with consensus oligonucleotide in a concentration-dependent manner. The activation of NF-kappaB by mixed cytokines was modulated both in the extent of activation and in its time-course by nepalolide A. 5 The ability of nepalolide A to inhibit NF-kappaB activation was further confirmed by studies on the degradation of the inhibitor of NF-kappaB, IkappaB, as measured by immunoblotting. 6 The present study demonstrates that the attenuation of NF-kappaB activation by nepalolide A was mediated by blockade of the degradation of IkappaB, leading to suppression of the expression of iNOS. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/10510444/Nepalolide_A_inhibits_the_expression_of_inducible_nitric_oxide_synthase_by_modulating_the_degradation_of_IkappaB_alpha_and_IkappaB_beta_in_C6_glioma_cells_and_rat_primary_astrocytes_ L2 - https://doi.org/10.1038/sj.bjp.0702785 DB - PRIME DP - Unbound Medicine ER -