Compositions and methods for modulating c-Rel-dependent cytokine production

Abstract

The present invention is directed to compositions and methods for modulating c-Rel-dependent cytokine production without materially altering the level of expression of NFκB and / or the amount of IκB. The present invention is also directed to screening for modulators of c-Rel activity as determined by assaying for altered subcellular localization of c-Rel but where the level of expression of NFκB and / or the amount of IκB is materially unaltered.

Description

[0001] This application claims the benefit of U.S. Provisional Patent Application Ser. Nos. 60 / 519,048 and 60 / 519,040, filed Nov. 10, 2003, and Nov. 11, 2003, respectively, which are incorporated by reference herein in their entirety.FIELD OF THE INVENTION [0002] The present invention is directed to compositions and methods for modulating c-Rel-dependent cytokine production without materially altering the level of expression of NFκB and / or amount of IκB. The present invention is also directed to screening for modulators of c-Rel activity as determined by assaying for altered subcellular localization of c-Rel but where the level of expression of NFκB and / or amount of IκB is materially unaltered. BACKGROUND OF THE INVENTION [0003] The role of cytokines in the development of autoimmune diseases and inflammatory disorders is well known. Cytokines such as interleukin-12 (IL-12) mediate the acute phase response to inflammatory stimuli, enhance the microbicidal functions of macrophages and...

AI Technical Summary

Benefits of technology

[0017] In one embodiment, a molecule identified in accordance with the methods of the invention as selectively altering c-Rel-dependent transcription and / or c-Rel-dependent cytokine production in a cell does not alter the level of expression and / or activity of one or more of the following proteins: PU-1, Jak1, Jak2, STAT1, ERK, PKA, IκB and p38 kinases. In another embodiment, a molecule identified in accordance with the methods of the invention as selectively altering c-Rel-dependent transcription and / or c-Rel-dependent cytokine production in a cell reduces the level of ICSBP in the nucleus. In a particular embodiment, a molecule identified in accordance with the methods of the invention as selectively altering c-Rel-dependent transcription and / or c-Rel-dependent cytokine production in a cell decreases in the level of interferon consensus sequence binding protein (ICSBP) in the nucleus of a cell by at least 10%, preferably, at least 15%, at least 18%, at least 20%<at least 25%, at least 30%, at least 35%, at least 40% or at least 45%.

[0018] In another embodiment, a molecule identified in accordance with the methods of the invention as selectively altering c-Rel-dependent transcription and / or c-Rel-dependent cytokine production in a cell reduces the level of p50 in the nucleus. In another embodiment, a molecule identified in accordance with the methods of the invention as selectively altering c-Rel-dependent transcription and / or c-Rel-dependent cytokine production in a cell increases the level of p65 in the nucleus. In a particular embodiment, a molecule identified in accordance with the methods of the invention as selectively altering c-Rel-dependent transcription and / or c-Rel-dependent cytokine production in a cell increases the level of p65 in the nucleus by at least 35%, preferably at least 40%, at least 45%, at least 50%, at least 55%, at least 59%, at least 60%, at least 65%, at least 70%, at least 75% or at least 85%. In another embodiment, a molecule identified in accordance with the methods of the invention as selectively altering c-Rel-dependent transcription and / or c-Rel-dependent cytokine production in a cell decreases p35 transcription. In yet another embodiment, a molecule identified in accordance with the methods of the invention as selectively altering c-Rel-dependent transcription and / or c-Rel-dependent cytokine production in a cell results in two or more of the following effects: a decrease in the level of ICSBP in the nucleus, a decrease in the level of p50 in the nucleus, an increase in the level of p65 in the nucleus, and a decrease in p35 transcription.

Problems solved by technology

It is presumed that after an infective or inflammatory stimulus that provokes IL-12 production, the powerful feedback loop promotes IL-12-induced IFN-γ, to further augment IL-12 production, leading to consequent excessive production of pro-inflammatory cytokines.

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