Control of the innate epithelial antimicrobial response is cell‐type specific and dependent on relevant microenvironmental stimuli

Abstract

SummaryImmune defence against microbes depends in part on the production of antimicrobial peptides, a process that occurs in a variety of cell types but is incompletely understood. In this study, the mechanisms responsible for the induction of cathelicidin and b-defensin antimicrobial peptides were found to be independent and specific to the cell type and stimulus. Vitamin D 3 induced cathelicidin expression in keratinocytes and monocytes but not in colonic epithelial cells. Conversely, butyrate induced cathelicidin in colonic epithelia but not in keratinocytes or monocytes. Distinct factors induced b-defensin expression. In all cell types, vitamin D 3 activated the cathelicidin promoter and was dependent on a functional vitamin D responsive element. However, in colonic epithelia butyrate induced cathelicidin expression without increasing promoter activity and vitamin D 3 activated the cathelicidin promoter without a subsequent increase in transcript accumulation. Induction of cathelicidin transcript correlated with increased processed mature peptide and enhanced antimicrobial activity against Staphylococcus aureus. However, induction of b-defensin-2 expression did not alter the innate antimicrobial capacity of cells in culture. These data suggest that antimicrobial peptide expression is regulated in a tissue-specific manner at transcriptional, post-transcriptional and post-translational levels. Furthermore, these data show for the first time that innate antimicrobial activity can be triggered independently of the release of other pro-inflammatory molecules, and suggest strategies for augmenting innate immune defence without increasing inflammation.

Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-γ genes and its association with susceptibility to tuberculosis

“…Thus, these data indicate that the 1,25(OH) 2 (9). Cathelicidins are relevant to defense against microbes including Gram-positive and -negative bacteria as well as fungi and certain viruses and it is increased with increasing concentrations of 1,25(OH) 2 D 3 (9). The addition of a VDR antagonist VAZ (ZK159222) inhibited the induction of cathelicidin mRNA by greater than 80%, and consequently the antimicrobial activity was reduced by about 70% (10).…”

“…This inhibits secretion of IL-12 and increases IL-10 production as well as inhibits the secretion interferon-γ (IFN-γ) and IL-2 by T cells and stimulates Th2 cell development with increased production of IL-4, IL-5, and IL-10 (7). Thus, these data indicate that the 1,25(OH) 2 (9). Cathelicidins are relevant to defense against microbes including Gram-positive and -negative bacteria as well as fungi and certain viruses and it is increased with increasing concentrations of 1,25(OH) 2 D 3 (9).…”

“…The activation of TLRs can also up-regulate the expression of vitamin D receptor and vitamin D-1-hydroxylase genes (enzyme that metabolizes 25(OH) 2 D 3 to 1,25(OH) 2 D 3 ), leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular M. tuberculosis (8). In addition, 1,25(OH) 2 D 3 , by itself, can modulate the immune response by its nuclear receptor (VDR), where it up-regulates protective immune host defense by induction of NOS (58) and cathelicidin (9) as well as down-regulation of IFN-γ gene expression by down-regulating its promoter (59). It is known that 1,25(OH) 2 D 3 is present 1000-fold less in peripheral blood than 25(OH) 2 D 3 , and the release of these forms in the granuloma space by VDBP may modulate T cell responses.…”

Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity

“…23 The broader applicability of this mechanism for injury-induced enhancement of 1,25 (OH) 2 D production with respect to barrier sites other than the skin remains unclear, and it is interesting to note that cells from the colon do not seem to induce cathelicidin in response to 1,25(OH) 2 D. 24 The basis for regulation of vitamin-D-induced innate immunity in keratinocytes also requires clarification, particularly in view of the 'feed-forward' induction of TLR expression by 1,25(OH) 2 D. One possible explanation for this regulation in keratinocytes is that (unlike macrophages), they show suppression of CP27B activity and induction of CP24A activity in response to 1,25(OH) 2 …”

Innate barriers against skin infection and associated disorders

“…In fact, it is thought that all life forms produce AMPs, such that even simple single cell organisms can gain a protective advantage in their environment. In human tissues such as skin or gut, the expression of AMPs can occur as part of the constitutive innate immune barrier, or can be increased when triggered by PRRs in response to injury or infection [10] [11]. AMP gene families in humans include the defensins and cathelicidins, first discovered in neutrophils and epithelia for their antimicrobial properties [12], and many other peptides and proteins originally known for activity as chemokines, enzymes, enzyme inhibitors and neuropeptides.…”