Vitamin D-Directed Rheostatic Regulation of Monocyte Antibacterial Responses

Abstract

In recent experiments, we have shown that activation of the TLR-2,1 signaling cascade by a 19 kDa lipopeptide from Mycobacterium tuberculosis (M. tb) increases expression of both CYP27b1 and VDR in monocyte/macrophages from normal human hosts (5). The resulting 1,25(OH) 2 D-VDR transcription complex is then able to stimulate expression of the cathelicidin antimicrobial protein (hCAP) with concomitant killing of phagocytosed mycobacteria. This induction of innate immune responses was hindered by incubation of TLR-stimulated human monocyte/macrophages with serum from vitamin D (25OHD)-insufficient subjects and rescued in vitro by the simple addition of supplemental 25OHD to medium conditioning those cells.Serum levels of 25OHD are a direct reflection of vitamin D "status," and several reports have highlighted the worldwide prevalence of 25OHD-insufficiency as a consequence of inadequate oral consumption or cutaneous biosynthesis of vitamin D (10, 11). In view of the link between 25OHD and macrophage function outlined above, we have proposed that populations with known susceptibility to vitamin D insufficiency may also exhibit impaired innate immunity. To test this hypothesis, we used cells and serum from a cohort of human subjects pre-and postvitamin D supplementation to assess various parameters associated with responses to TLR activation. Data reveal a direct correlation between serum concentration of 25OHD and monocyte expression of hCAP following treatment with ligands to pathogen-responsive TLRs. Furthermore, we show that in vivo supplementation of vitamin D insufficient patients significantly enhanced ex vivo innate immune responses by rescuing TLRmediated suppression of hCAP expression.

Vitamin D and Human Pregnancy

“…This was confirmed by studies using monocytes cultured in medium supplemented with serum from vitamin D-sufficient Caucasian donors which showed much higher levels of M. tb-induced cathelicidin expression relative to monocytes cultured with serum from vitamin D-insufficient African-Americans 131 . Similar observations have also been made using serum from vitamin D-insufficient subjects supplemented with vitamin D to restore optimal vitamin D status 136 . Importantly, the effect of vitamin D supplementation is dependent on elevated circulating levels of 25OHD, with no change in serum levels of 1,25(OH) 2 D being observed 136 .…”

“…Similar observations have also been made using serum from vitamin D-insufficient subjects supplemented with vitamin D to restore optimal vitamin D status 136 . Importantly, the effect of vitamin D supplementation is dependent on elevated circulating levels of 25OHD, with no change in serum levels of 1,25(OH) 2 D being observed 136 . Although these studies have shown that vitamin D status is a key determinant of the magnitude of innate immune responses to infection, it is likely that other factors will also influence this activity.…”

Vitamin D and the Regulation of Placental Inflammation

“…Asterisks denote statistically different from LPS-treated placentas with a Cyp27b1 +/+ genotype. *p , 0.05, **p , 0.01, ***p , 0.001. activation of TLR2/1 (18,22). However, to date, there has been no report of TLR-mediated activation of Cyp27b1 and VDR in vivo.…”

“…Data highlight a role for vitamin D as a potent regulator of inflammation in the placenta, and this may be a key factor linking vitamin D with pathological conditions such as pre-eclampsia. However, it is important to recognize that vitamin D is also able to influence other aspects of immunity, notably the stimulation of antibacterial innate immune responses (18,22). In previous studies using human tissue, we have shown that induction of the antimicrobial protein cathelicidin by vitamin D is not restricted to the immune system but can also be observed with cells from both the maternal and fetal sides of the placenta (11,12).…”

“…Regulation of the vitamin D system after TLR activation has been reported previously for several cell types. In vitro, the TLR4 ligand LPS is known to stimulate 1a-hydroxylase expression or activity in macrophages (17), monocytes (18), and dendritic cells (19), as well as kidney distal tubule cells (20) and endothelial cells (21). In monocytes, the TLR2 ligand 19-kDa lipoprotein stimulates expression of both CYP27B1 and VDR, providing an intracrine mechanism for vitamin D responses after .…”