Abstract
Postpartum, infants have not yet established a fully functional adaptive immune system and are at risk of acquiring infections. Hence, newborns are dependent on the innate immune system with its antimicrobial peptides (AMPs) and proteins expressed at epithelial surfaces. Several factors in breast milk are known to confer immune protection, but which the decisive factors are and through which manner they work is unknown. Here, we isolated an AMP-inducing factor from human milk and identified it by electrospray mass spectrometry and NMR to be lactose. It induces the gene (CAMP) that encodes the only human cathelicidin LL-37 in colonic epithelial cells in a dose- and time-dependent manner. The induction was suppressed by two different p38 antagonists, indicating an effect via the p38-dependent pathway. Lactose also induced CAMP in the colonic epithelial cell line T84 and in THP-1 monocytes and macrophages. It further exhibited a synergistic effect with butyrate and phenylbutyrate on CAMP induction. Together, these results suggest an additional function of lactose in innate immunity by upregulating gastrointestinal AMPs that may lead to protection of the neonatal gut against pathogens and regulation of the microbiota of the infant.
Highlights
The adaptive immune system of infants lacks antibodies specific for common pathogenic microbes and is deficient in differentiated immune cells [1]
Colonic epithelial cell lines Caco-2 and T84, THP-1 monocytes/macrophages, and the bronchial epithelial cell line VA-10 were assayed for cathelicidin antimicrobial peptide (CAMP) gene expression after stimulation with the hydrophilic fraction
THP-1 macrophages stimulated with 5 g/l of hydrophilic fraction resulted in a 3.2-fold CAMP gene induction (** p#0.005) after 24 h, while stimulation of THP-1 macrophages with 50 g/l hydrophilic fraction resulted in lower induction of CAMP gene (Fig. 2D)
Summary
The adaptive immune system of infants lacks antibodies specific for common pathogenic microbes and is deficient in differentiated immune cells [1]. Neonates must establish their microbiota in order to generate a balance between immune defense and tolerance [3] During this prolonged and sensitive period infants are susceptible to infections such as diarrheal diseases, one of the leading causes of child mortality [4]. It is established that breast-fed infants harbor better immune defenses against several types of infections [14] and exhibit lower frequencies of inflammatory diseases than formula-fed infants [15,16]. This implies that milk, apart from being a nutritional source, can augment the immune defense of infants. Studies on immunological factors of human breast milk have mainly focused on direct antimicrobial effects (reviewed in [10]) and less on the capacity to modulate the expression of infant immune genes
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