Glucagon-like peptide-2 (GLP-2) is a pleiotropic peptide secreted in the
human intestine with known intestinotrophic properties beneficial in conditions
like short bowel syndrome (SBS); a condition characterized by malabsorption
of both fluid and nutrients. Left untreated, SBS can lead to dehydration,
malnutrition, and weight loss. Teduglutide, a long acting analogue of GLP-2,
has been used in multiple clinical studies to elucidate its trophic properties.
Murine studies however have also shown that GLP-2 inhibits pro-inflammatory
cytokines raising the possibility of an anti-inflammatory property and its
potential use in intestinal inflammatory conditions; in particular inflammatory
bowel disease (IBD). Dendritic cells (DC) play a central role in the initiation
and regulation of the immune system. They bridge the innate and adaptive
immune systems and are unique in their ability to activate naïve T cells as
well as dictate the type of T-cell immunity.
We hypothesized that GLP-2 has an immunomodulatory role and exert this
action via DC. Toxic effects of GLP-2 peptide on human DC in-vitro have not
previously been experimented. Our experiments showed that GLP-2 did not
have a toxic effect on DC at 1pM, 1nM and 1μM concentrations and hence we
were subsequently able to look at the effects of GLP-2 on human DC
phenotype and function. Using whole blood and intestinal biopsies from
healthy volunteers, we obtained a population of enriched low density cells
(LDC) which offered a novel and ‘physiological’ model for DC. These cells
were labelled with appropriate fluorochromes and assayed by a flow
cytometer.
We established that DC incubated overnight with GLP-2 had a reduced
intensity ratio of HLA DR and an increased expression of CD14 in a dose
dependent way compared with controls. The expression of co-stimulatory
molecule CD86 was also higher in the treated DC. This phenotypic change
suggests that GLP-2 modulated DC into an immature state although still able
to stimulate T-cell proliferation. Ongoing cytokine production of IFN-γ and IL-
12 from healthy blood DC was inhibited by GLP-2 however only cytokine
production of IFN-γ from intestinal lamina propria DC was inhibited. These
findings suggest that GLP-2 may induce a ‘homeostatic’ or ‘immuno-tolerant’
state and block Th1 cytokines in DC.
Functional experiments confirmed that GLP-2 modulated DC enhanced T cell
proliferation although this occurred only with intestinal DC. GLP-2 conditioned
DC also functionally affected the cytokine profile of T cells by reducing the
cytokines IFN-γ in both human blood and intestinal DC and IL-12 in only the
latter. Hence our human DC in-vitro findings mirror some of the results found
in murine studies showing GLP-2 effects on blocking Th1 cytokines. The
results suggest that GLP-2 has an immunoregulatory effect and that the
mechanism of action may possibly involve direct effects on DC. GLP-2
therefore is able to modulate DC characteristics and function leading to future
application as an immunotherapy for inflammatory diseases.