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

Convergence of Additional Signal Pathways with Vitamin D Modulate Antimicrobial Peptide Gene Expression

Activation of TLRs promotes the release of immunomodulatory cytokines that play a role in the innate immune response. Once such cytokine, IL-15, was shown to be required for TLR2/1 induction of cathelicidin and also found to be sufficient to activate the vitamin D pathway in macrophages.[98] The in vivo importance of IL-15 remains to be elucidated, but it may provide a mechanism to activate the vitamin D pathway in neighboring monocytes and macrophages, thus amplifying the innate immune response.[98]

In conditions such as psoriasis, lesions contain significant levels of inflammatory cytokines. IL-17A is present at high levels in psoriatic lesions owing to an enrichment of Th17 cells, and LL-37 and HBD2 are present at high levels in psoriatic lesions and may contribute to the development of the disease.[61,99] Recently, it was described that the LL-37 peptide converts self-DNA and self-RNA from dying host cells into a trigger of TLR9, -7 and -8 in human DCs, thus providing new insights into the mechanism that drives the autoimmune responses in psoriasis.[99,100] In human keratinocytes it was found that IL-17A enhances expression of the CAMP gene via activation of Act1 and MEK–ERK in a process that is dependent on the presence of 1,25(OH)2D.[101] HBD2 and HBD3 have been shown to be regulated by IL-22 and -17A via JAK-STAT and NF-κB pathways.[102,103] These findings elucidate a mechanism for cytokine-mediated inflammation in psoriatic skin through increased antimicrobial peptide expression. Interestingly, vitamin D analogs are used to successfully treat psoriasis and do not exacerbate the disease. Elucidation of the effects of vitamin D analogs on the cytokine milieu of the lesion or on keratinocyte differentiation may provide clues that explain this apparent paradox. Peric et al. recently reported that topical application of vitamin D and vitamin D analogs reduced expression of IL-17A, IL-17F and IL-8 in psoriatic lesions as well as the antimicrobial peptides HBD2 and HBD3.[104] The vitamin D analogs blocked HBD2 induction by IL-17 by inhibition of NF-κB signaling.[104] By contrast, levels of CAMP mRNA were increased in the lesions. In human primary keratinocytes in vitro, the unprocessed 18-kD form of the protein, hCAP18, was induced by vitamin D and its analogs, but the processed peptide LL-37, which plays a critical role in the development of psoriasis, was not detected by western blot analysis.[104] The authors postulated that the induction of hCAP18 may not be accompanied by an increase in the active LL-37 peptide owing to a lack of processing. It remains to be determined if hCAP18 processing into LL-37 is altered in psoriatic skin lesions treated with active vitamin D and its analogs, but the hypothesis is testable and may explain why vitamin D does not exacerbate psoriasis.

While some cytokines may boost CAMP gene expression, others may inhibit it. In atopic dermatitis patients, the expression level of CAMP is found to be relatively low when compared with psoriasis patients.[61] The reduced expression may be due to Th2-type cytokines, such as IL-4, -10 and -13, which are abundant in atopic dermatitis skin, inducing Bcl-3, a transcriptional regulator that represses CAMP gene expression.[105]

The involvement of additional signaling pathways in the induction of antimicrobial peptide gene expression is especially important for induction of the DEFB4 gene. The focus on cathelicidin gene expression has been due, in large part, to its robust and easily detected expression by 1,25(OH)2D treatment alone. This was not the case for the DEFB4 gene [GOMBART AF, UNPUBLISHED DATA]. A recent report demonstrated in vitro that induction of the DEFB4 gene in macrophages requires TLR activation and the convergence of the IL-1β and vitamin D pathways.[97]

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