Abstract
hCAP18/LL-37 is the sole human cathelicidin; a family of host defence peptides with key roles in innate host defence. hCAP18/LL-37 is expressed primarily by neutrophils and epithelial cells, but its production and function in the lower genital tract is largely uncharacterised. Despite the significant roles for cathelicidin in multiple organs and inflammatory processes, its impact on infections that could compromise fertility and pregnancy is unknown. The aim of this study was to investigate cathelicidin production, regulation and function in the cervix. hCAP18/LL-37 was found to be present in cervicovaginal secretions collected from women in the first trimester of pregnancy and to be expressed at significantly higher levels in samples from women with alterations in vaginal bacterial flora characteristic of bacterial vaginosis. In endocervical epithelial cell lines, expression of the gene encoding hCAP18/LL-37 (CAMP) was not affected by TLR agonists, but was found to be up-regulated by both 1, 25 hydroxyvitamin D3 and 25 hydroxyvitamin D3. However, no association was found between serum levels of vitamin D and hCAP18/LL-37 concentrations in cervicovaginal secretions (n = 116). Exposure to synthetic LL-37 had a pro-inflammatory effect on endocervical epithelial cell lines, increasing secretion of inflammatory cytokine IL-8. Together these data demonstrate inducible expression of hCAP18/LL-37 in the female lower reproductive tract in vivo and suggest the capacity for this peptide to modulate host defence to infection in this system. Further investigation will elucidate the effects of hCAP18/LL-37 on the physiology and pathophysiology of labour, and may lead to strategies for the prevention of infection-associated preterm birth.
Highlights
Cathelicidins are an evolutionary conserved family of multifunctional host defence peptides (HDP) [1]. hCAP18/LL-37 is the sole human cathelicidin and has important roles in innate host defence [2]
To investigate whether neutrophils were the main source of hCAP18/LL-37 we examined the correlation between myeloperoxidase (MPO), a neutrophil granule product, and hCAP18/LL37
A weak positive correlation was found between cervicovaginal MPO and cervicovaginal hCAP18/LL-37 (r = 0.1; n = 77, p = 0.3), the limited strength suggesting that neutrophils were not the predominant source of hCAP18/LL-37 (Figure 1A)
Summary
Cathelicidins are an evolutionary conserved family of multifunctional host defence peptides (HDP) [1]. hCAP18/LL-37 is the sole human cathelicidin and has important roles in innate host defence [2]. Cathelicidins are an evolutionary conserved family of multifunctional host defence peptides (HDP) [1]. HCAP18/LL-37 is the sole human cathelicidin and has important roles in innate host defence [2]. Expressed by neutrophils and epithelial cells, hCAP18/LL-37 expression can be induced by bacterial products and inflammatory stimuli [3,4], and can be regulated by vitamin D3 [5,6]. Epithelial cells of the vagina and cervix create a physical barrier to infection, and the normal vaginal population of lactobacilli create an inhospitable environment for invading pathogens [10]. HDP have been shown to be critical to the ability of the cervix to prevent ascending infection [13]
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