Multifunctional activity of a small tellurium redox immunomodulator compound, AS101, on dextran sodium sulfate-induced murine colitis.
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.
From the C.A.I.R. Institute, Safdié AIDS and Immunology Research Center, Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Gilad
G
Halpert
From the C.A.I.R. Institute, Safdié AIDS and Immunology Research Center, Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Tom
T
Eitan
the Shraga Segal Department of Microbiology and Immunology, and Faculty of Health Sciences and Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Elena
E
Voronov
the Shraga Segal Department of Microbiology and Immunology, and Faculty of Health Sciences and Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Ron N
RN
Apte
the Department of Pathology, Rabin Medical Center, Golda Campus, Petah Tikva 49372, Israel, the Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel, and.
Lea
L
Rath-Wolfson
Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Michael
M
Albeck
From the C.A.I.R. Institute, Safdié AIDS and Immunology Research Center, Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Yona
Y
Kalechman
From the C.A.I.R. Institute, Safdié AIDS and Immunology Research Center, Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel, srednib@gmail.com.
Benjamin
B
Sredni
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D005030:Ethylenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009088:Mucoproteins; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D015815:Cell Adhesion Molecules; D005030:Ethylenes; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007155:Immunologic Factors; D020381:Interleukin-17; D053583:Interleukin-1beta; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D007371:Interferon-gamma; D016264:Dextran Sulfate; D051057:Proto-Oncogene Proteins c-akt
AS101; Cytokine; DSS; Immunomodulator; Inflammation; Inflammatory Bowel Disease (IBD); Innate Immunity; Interleukin 17; Interleukin 1beta; Intestine