Statins influence epithelial expression of the anti-microbial peptide LL-37/hCAP-18 independently of the mevalonate pathway

Abstract

Anti-microbial resistance increases among bacterial pathogens and new therapeutic avenues needs to be explored. Boosting innate immune mechanisms could be one attractive alternative in the defence against infectious diseases. The cholesterol-lowering drugs, statins, have been demonstrated to also affect the immune system. Here we investigate the effect of statins on the expression of the human cathelicidin anti-microbial peptide (CAMP) LL-37/hCAP-18 [encoded by the CAMP gene] and explore the underlying mechanisms in four epithelial cell lines of different origin. Simvastatin induced CAMP expression in bladder epithelial cells telomerase-immortalized uroepithelial cells (TERT-NHUCs), intestinal cells HT-29 and keratinocytes HEKa, but not in airway epithelial cells A549. Gene induction in HEKa cells was reversible by mevalonate, while this effect was independent of the cholesterol biosynthesis pathway in TERT-NHUCs. Instead, inhibition of histone deacetylases by simvastatin seems to be involved. For HT-29 cells, both mechanisms may contribute. In addition, simvastatin increased transcription of the vitamin D-activating enzyme CYP27B1 which, in turn, may activate LL-37/hCAP-18 production. Taken together, simvastatin is able to promote the expression of LL-37/hCAP-18, but cell line-specific differences in efficacy and the involved signalling pathways exist.

Significance of LL-37 on Immunomodulation and Disease Outcome

“…Different factors by different incentives from the body and outside can influence this peptide expression, for example, interferon γ (IFN-γ), interleukin 6 (IL-6), glucocorticoids, transmigration across activated endothelium, bacterial exotoxins, certain bacteria, entitystat, and calcipotriol are found to be the downregulated factors [10], while the upregulation of expression was found to be tumor necrosis factor α (TNF-α), IL-17A, toll-like receptor agonists, insulin-like growth factor 1 (IGF-1), vitamin D receptor agonists, hormonal 1,25dihydroxyvitamin D, phenyl butyrate, sodium butyrate, MUC2 mucin, simvastatin, injury and wounding, and endoplasmic reticulum stress [10,18,19].…”

Metformin strengthens uroepithelial immunity against E. coli infection

“…Therefore, strengthening the host immunity by modulatory drugs can be an alternative approach to fight infections. In the quest for such immune stimulatory compounds, we have previously demonstrated improvement of uroepithelial cell immunity by estrogen 4 , vitamin D 7 , simvastatin 8 , and traditional herbal extracts 9 . Here, we have explored the possibility of repurposing metformin ( N , N -dimethylbiguanide), a frequently used anti-diabetic drug with glucose lowering effects 10 as a therapeutic option against uropathogenic E. coli .…”

Atorvastatin inhibits the proliferation of MKN45-derived gastric cancer stem cells in a mevalonate pathway-independent manner

“…Although statins are approved only for the treatment of hypercholesterolemia, increasing evidence suggests that they are useful against other diseases, including cancer [ 23 - 25 ]. Atorvastatin is administered as a clinical treatment for hypercholesterolemia at 10–80 mg/day [ 26 ].…”