Will vitamin D supplementation ameliorate diseases characterized by chronic inflammation and fatigue?

Chronic NF-κB activation has been supposed as a key event in chronic fatigue syndrome (CFS) and many other better-defined pro-inflammatory diseases. Knowledge about the impact of deficiency vitamin D on chronic NF-κB activation could open a new disease approach. Whereas NF-κB activation leads at first to a pro-inflammatory immune response, later on a vitamin D-dependent anti-inflammatory response ensues. Binding of the active vitamin D metabolite 1,25(OH)(2)D(3) to vitamin D receptor (VDR) yields a transcription factor which represses NF-κB activation, and additionally modulates and down-regulates adaptive, but enhances innate immune responses, and improves redox balance, thus counterbalancing inflammation on multiple levels. However, this built-in late counterbalance against inflammation works only when stores of calcium and 25(OH)D(3) are abundant. Therefore a connection between lowered vitamin D-metabolism and persistent NF-κB activation, augmented nitrosative-oxidative stress, redox imbalance, chronic inflammation, and concomitant fatigue can be postulated. In order to confirm this hypothesis, randomized controlled clinical studies about the clinical effects of supplementation of calcium and vitamin D(3) would be necessary in diseases characterized by persistent NF-κB activation and chronic inflammation and fatigue.