The cytokine and endocannabinoid systems are co-regulated by NF-κB p65/RelA in cell culture and transgenic mouse models of Huntington's disease and in striatal tissue from Huntington's disease patients

• p65/RelA and p65/RelA-regulated genes were analyzed in Huntington's disease (HD).
• CB1, IL-1β, IL-8, CCL5, GM-CSF, MIP-1β, and TNFα levels were decreased in HD.
• The promoter of each of these genes contains multiple putative p65/RelA elements.
• CB1 activation restored CCL5 expression in a cell mode of HD via p65/RelA.
• CB1-specific cannabinoids may normalize p65/RelA-dependent gene expression in HD.

Transcriptional dysregulation is a major pathological feature of Huntington's disease (HD). The goal of this study was to understand how p65/RelA co-regulated genes, specifically those of the cytokine and endocannabinoid systems, were affected in HD. p65/RelA levels were lower in human HD tissue and R6/2 HD mice, as were the levels of the type 1 cannabinoid receptor (CB1), IL-1β, IL-8, CCL5, GM-CSF, MIP-1β, and TNFα, all of which may be regulated by p65/RelA. Activation of p65/RelA restored CB1 and CCL5 expression in STHdh cell models of HD. Therefore, p65/RelA activation may normalize the expression of some genes in HD.