Abrogated lymphocyte infiltration and lowered CD14 in dextran sulfate induced colitis in mice treated with p65 antisense oligonucleotides

Dextran sulfate sodium (DSS) induced colitis exhibits a predominantly NF-kappaB dependent proinflammatory cytokine profile and shares similarities with human inflammatory bowel disease (IBD). Lamina propria macrophages of IBD patients display elevated levels of NF-kappaB p65. Knowing the role of NF-...

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Bibliographic Details
Published in:International journal of colorectal disease 2002-07, Vol.17 (4), p.223-232
Main Authors: SPIIK, Ann-Kristin, RIDDERSTAD, Anna, AXELSSON, Lars-Göran, MIDTVEDT, Tore, BJÖRK, Lars, PETTERSSON, Sven
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Colitis - chemically induced
Colitis - immunology
Colitis - therapy
Dextran Sulfate
Female
Humans
Immunomodulators
Lipopolysaccharide Receptors - immunology
Lymphocytes - immunology
Male
Medical sciences
Medicin och hälsovetenskap
Mice
NF-kappa B - drug effects
NF-kappa B - immunology
Oligonucleotides, Antisense - therapeutic use
Pharmacology. Drug treatments
Time Factors
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Summary:Dextran sulfate sodium (DSS) induced colitis exhibits a predominantly NF-kappaB dependent proinflammatory cytokine profile and shares similarities with human inflammatory bowel disease (IBD). Lamina propria macrophages of IBD patients display elevated levels of NF-kappaB p65. Knowing the role of NF-kappaB in IBD, we investigated the beneficial cellular mechanisms underlying the lasting effect of a single p65 antisense treatment in DSS-colitis mice. One local dose of p65 antisense oligonucleotides was administered in DSS colitis mice. Ten days later the mice were killed and examined at cellular and biochemical levels. The level of p65 in lamina propria cells was determined by electrophoretic mobility shift assay and by intracellular immunofluorescent staining of nuclear p65 levels, using laser scanning cytometer. FACS analysis demonstrated a considerable drop in infiltrating lymphocytes and a drastic reduction in CD14+ cells in mice treated with p65 antisense oligonucleotides. Moreover, abrogation of inflammation extended all the way to the cecum in treated mice. Treatment was correlated with decreased DNA binding activity of NF-kappaB. Our data strongly support a model in which p65 antisense treatment possesses the capacity to disrupt the pathogenic autocrine loop propagated by NF-kappaB at the chronic phase of IBD.
ISSN:0179-1958
1432-1262
DOI:10.1007/s00384-001-0366-3