High concentrations of kC may also arise from dietary intake

High concentrations of 7kC may also arise from dietary intake of processed cholesterol-rich food, likely favoring or worsening inflammatory bowel disease (IBD) [5,13]. Furthermore, IBD has been associated with a dysregulation of colonic 11β-HSD expression, exhibiting increased 11β-HSD1 and decreased 11β-HSD2 levels [[44], [45], [46], [47]]. Importantly, colonic inflammation has been shown to locally upregulate the tlr4 for 7α25OHC production and thereby activate the EBI2 pathway [48]. In such a situation of high 7kC levels and CH25H expression, substantial amounts of 7k25OHC may be generated, which in turn can be further metabolized by the upregulated 11β-HSD1 to 7β25OHC. In contrast, 11β-HSD2 that converts 7β25OHC to 7k25OHC and likely represents a protective mechanism is downregulated. The formed 7β25OHC may then act as an EBI2 ligand, although less potent than 7α25OHC, as outlined in the following. First, 7β25OHC, produced at sites of acute inflammation at relatively high concentrations, may function as a danger signal to initiate EBI2 response. In such a situation, 7kC may serve as a first line danger initiator, a hypothesis supported by mRNA expression studies showing a highly dynamic regulation of the enzymes necessary for oxysterol synthesis [49]. Primary human monocytes and macrophages express low levels of CH25H and even more limited CYP7B1, which is required for 7α-hydroxylation of 25OHC. Following an immune challenge, immediate and pronounced up-regulation of CH25H mRNA levels were observed, compared to a delayed rise of CYP7B1 in M0 macrophages. Hence, 7β25OHC may control EBI2-mediated immune cell migration under oxidative stress in a first step, followed by an adaptive response through signaling via the more potent 7α25OHC. Second, in case of persisting oxidative stress, production of 7β25OHC will continue and maintain an EBI2 response. In particular, in chronic inflammation, 7β25OHC may thus prolong immune cell migration and exacerbate tissue damage. In this regard, the inhibition or the deficiency of 11β-HSD1 should exert beneficial effects on the resolution of inflammation. Indeed, 11β-HSD1 depletion was shown to improve chronic metabolic inflammation (atherosclerosis, diabetes, obesity; reviewed in [50]). Interestingly, two genetic mouse models of obesity showed increased hepatic 25OHC levels accompanied by increased CH25H and decreased CYP7B1 mRNA levels [51]. Moreover, the same study described a pronounced decrease of hepatic CYP7B1 expression in a diet-induced obesity model over time. Therefore, 7β25OHC levels might rise over time compared to 7α25OHC. This, however, also depends on the efficiency of degradation and further metabolism of 7α25OHC and 7β25OHC. Finally, it has to be considered that the EBI2 ligand 7β25OHC will not act alone but in addition to 7α25OHC, thereby possibly leading to saturating concentrations of EBI2 ligand and resulting in receptor desensitization with a loss of cell migration [52]. One proposed mechanism might not exclude the others, depending on the disease state; however, all hypotheses require careful and thorough experimental investigation. In general, the involvement of a cell membrane receptor suggests rather a paracrine than an intracrine regulation of EBI2 by 11β-HSDs. Crucially, effects depending on 11β-HSD2 cannot be evaluated using mouse models due to the considerable species-specific differences identified for this enzyme ([29,53], current study). 7,25-dioxygenated oxysterols are not only subjected to an 11β-HSD-dependent metabolism, but they can affect the metabolic interconversion of active and inactive glucocorticoids by competition in the substrate binding pocket and thus inhibiting 11β-HSD1 and 2. Whereas the inhibition of the human 11β-HSD1-dependent oxoreduction of cortisone is rather weak (IC50 value of 405 nM for 7k25OHC) and less likely to be of physiological relevance, the oxidation of cortisol to cortisone by human 11β-HSD2 can be potently inhibited by both 7k25OHC and 7β25OHC (IC50 values of 49 nM and 91 nM respectively). Moreover, 7k25OHC and 7β25OHC belong to the most potent endogenous 11β-HSD2 inhibitors identified so far [54]. Thus, an involvement of 7,25OHCs in 11β-HSD2-dependent essential hypertension as so-called glycerrhetinic acid-like factors (GALFs) [54] seems more likely than regulating glucocorticoid-dependent inflammatory responses, thus warranting further research.