The transcription factor NFκB is a central regulator of inflammation and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFkB. Here, we report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after TNFα stimulation. Both variants result in increased degradation of IκBα, a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway TNFAIP3, BCL3, and CIAP1. Finally naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.
The ability to decide advantageously among options that vary in both their risks and rewards is critical for survival and well-being. Previous work shows that some forms of risky decision making are robustly modulated by monoamine signaling, but it is less clear how monoamine signaling modulates decision making under risk of explicit punishment. The goal of these experiments was to determine how this form of decision making is modulated by dopamine, serotonin, and norepinephrine signaling, using a task in which rats choose between small, “safe” food rewards and large food rewards associated with variable risks of punishment. Preference for the large, risky reward (risk taking) was reduced by administration of a D2/3 dopamine receptor agonist (bromocriptine) and a selective D2 agonist (sumanirole). The selective D3 agonist PD128907 appeared to attenuate reward discrimination abilities, but did not affect risk taking per se. In contrast, drugs targeting serotonergic and noradrenergic signaling had few if any effects on choice behavior. These data suggest that in contrast to other forms of risky decision making, decision making under risk of punishment is selectively modulated by dopamine signaling, predominantly through D2 receptors.
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