Received for publication July 3, 2006.
Revised August 18, 2006.
Accepted for publication August 29, 2006.

Eriocalyxin B inhibits NF-B activation by interfering with the binding of both p65 and p50 to the response element in a non-competitive manner

Abstract

NF-B has been recognized to play a critical role in cell survival and inflammatory processes. It has become a target for intense drug development for the treatment of cancer, inflammatory and autoimmune diseases. Here we describe a potent NF-B inhibitor, eriocalyxin B (Eri-B), an ent-kauranoid isolated from Isodon eriocalyx, an anti-inflammatory remedy. The presence of two ,-unsaturated ketones give this compound the uniqueness among the ent-kauranoids tested. Eri-B inhibited the NF-B transcriptional activity but not that of CREB. It suppressed the transcription of NF-B downstream gene products including cyclooxygenase-2 and inducible nitric oxide synthase induced by TNF- or LPS in macrophages and hepatocarcinoma cells. Chromatin immunoprecipitation assay indicated that Eri-B selectively blocked the binding between NF-B and the response elements in vivo without affecting the nuclear translocation of the transcription factor. Down-regulation of the endogenous p65 protein sensitized the cells towards the action of the compound. Furthermore, in vitro binding assays suggested that Eri-B reversibly interfered with the binding of p65 and p50 subunits to the DNA in a non-competitive manner. In summary, this study reveals the novel action of a potent NF-B inhibitor that could be potentially used for the treatment of a variety of NF-B associated diseases. Modification of the structure of this class of compounds becomes the key to the control of the behavior of the compound against different cellular signaling pathways.

Key words: Nitric oxide synthases, Tumor necrosis factor, AP-1, CREB, NFkappaB, DNA binding sites

This article has been cited by other articles:

				V. M. Abrahams, P. B. Aldo, S. P. Murphy, I. Visintin, K. Koga, G. Wilson, R. Romero, S. Sharma, and G. Mor TLR6 Modulates First Trimester Trophoblast Responses to Peptidoglycan J. Immunol., May 1, 2008; 180(9): 6035 - 6043. [Abstract] [Full Text] [PDF]