The Vitamin D–antimicrobial Peptide Pathway and Its Role in Protection against Infection

Adrian F Gombart

Disclosures

Future Microbiol. 2009;4(9):1151-1165. 

In This Article

Therapeutic Applications

Increasing endogenous cathelicidin (hCAP18/LL-37) expression may offer advantages over simple administration of synthetic antimicrobial peptides; transient expression of hCAP18 protein by adenovirus was tenfold more effective than synthetic peptide in preventing bacterial growth on second-degree burns in a mouse model.[119] Also, induction of CAMP with butyrate treatment in Shigella-infected rabbits improved their outcome.[120,121] Thus, hCAP18 may aid in clearance of bacterial infection and protect against sepsis. Administration of synthetic hCAP18/LL-37 may be beneficial, but because butyrate-[120] or adenoviral vector-induced increases in endogenous hCAP18 produced markedly improved outcomes, we propose that interventions that increase endogenous hCAP18 levels may be particularly useful in the treatment of infections.

Our own research has shown that high levels of hCAP18 in the blood of hemodialysis patients at the start of their treatment was indicative of a significant decrease in 1-year mortality.[122] There was modest correlation with 1,25(OH)2D levels, but not with 25(OH)D levels.[122] In a recent study with sepsis patients, an association was found between severe illness and lower 25(OH)D, DBP and cathelicidin levels as compared with healthy controls.[123] A positive correlation between 25(OH)D and cathelicidin levels was observed in all subjects.[123] The question of whether increased supplementation of vitamin D-deficient individuals with 25(OH)D or therapeutic treatment of patients with active analogs of 1,25(OH)2D will boost plasma levels of cathelicidin remains to be seen.

A study in atopic dermatitis patients demonstrated that supplementation with 4000 international units (IU)/day of oral vitamin D for 21 days increased cathelicidin expression in the lesional skin with a mild increase in the normal skin.[124] We found that supplementation with 50,000 IU two times per week for 5 weeks had no effect on circulating levels of cathelicidin; however, it should be noted that the individuals in this study were relatively vitamin D replete and no patients were deficient. Thus, it is possible that circulating cathelicidin levels may be more dependent on vitamin D status at very low levels of serum 25(OH)D.[97] In this same study, we did demonstrate that the ability of human macrophages to induce cathelicidin expression in response to TLR activation was directly proportional to serum vitamin D status. Cathelicidin induction was enhanced in vitamin D-insufficient patients given supplementary vitamin D.[97] The studies to date would argue that it is important for individuals to have sufficient serum levels of 25(OH)D to allow cells in the body to synthesize cathelicidin when needed.

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