Abstract
Inflammatory bowel diseases (IBDs) are a group of idiopathic, chronic immune-mediated diseases characterized by an aberrant immune response, including imbalances of inflammatory cytokine production and activated innate and adaptive immunity. Selective blockade of leukocyte migration into the gut is a promising strategy for the treatment of IBD. This study explored the effect of the immunomodulating tellurium compound ammonium trichloro (dioxoethylene-o,o') tellurate (AS101) on dextran sodium sulfate (DSS)-induced murine colitis. Both oral and intraperitoneal administration of AS101 significantly reduced clinical manifestations of IBD. Colonic inflammatory cytokine levels (IL-17 and IL-1β) were significantly down-regulated by AS101 treatment, whereas IFN-γ was not affected. Neutrophil and α4β7(+) macrophage migration into the tissue was inhibited by AS101 treatment. Adhesion of mesenteric lymph node cells to mucosal addressin cell adhesion molecule (MAdCAM-1), the ligand for α4β7 integrin, was blocked by AS101 treatment both in vitro and in vivo. DSS-induced destruction of colonic epithelial barrier/integrity was prevented by AS101, via up-regulation of colonic glial-derived neurotrophic factor, which was found previously to regulate the intestinal epithelial barrier through activation of the PI3K/AKT pathway. Indeed, the up-regulation of glial-derived neurotrophic factor by AS101 was associated with increased levels of colonic pAKT and BCL-2 and decreased levels of BAX. Furthermore, AS101 treatment reduced colonic permeability to Evans blue and decreased colonic TUNEL(+) cells. Our data revealed multifunctional activities of AS101 in the DSS-induced colitis model via anti-inflammatory and anti-apoptotic properties. We suggest that treatment with the small, nontoxic molecule AS101 may be an effective early therapeutic approach for controlling human IBD.
Highlights
AS101, a novel small tellurium compound, is a potent anti-inflammatory/anti-apoptotic immunomodulator
mucosal addressin cell adhesion molecule (MAdCAM)-1 is constitutively expressed by mucosal endothelial cells of PPs, mesenteric lymph nodes (MLNs), and lamina propia (LP) of the small and large intestine [50]
Interrupting the ␣47-MAdCAM-1 interaction in the MLN upon AS101 treatment and the ability of AS101 to block the migration of ␣47ϩ inflammatory cells into the colon further demonstrates the clinical importance of this interaction
Summary
AS101, a novel small tellurium compound, is a potent anti-inflammatory/anti-apoptotic immunomodulator. Peripheral blood mononuclear cells obtained from patients with Crohn disease were shown to produce high levels of IL-1 in vitro compared with normal control cells [13], and enhanced secretion of IL-1 was shown in colonic biopsies from patients with inflammatory bowel disease [12, 14] Based on these findings, several cytokine-based therapies have been developed and tested for the treatment of IBD patients [6, 15]. Feeding mice with polymeric dextran sodium sulfate (DSS) in their drinking water induces acute or chronic colitis characterized by bloody diarrhea, ulceration, loss of body weight, and infiltration with granulocytes or mononuclear cells, reflecting IBD symptoms [18] This widely used murine colitis model is helpful for studying the effect of novel therapeutic agents for the management of IBD [19]. Our findings revealed anti-inflammatory and anti-apoptotic properties of AS101 through the down-regulation of colonic inflammatory cytokine levels, prevention of inflammatory cell migration into the tissue, and inhibition of colonic apoptotic processes
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