Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.

Details

Serval ID
serval:BIB_2EE7B9C790F8
Type
Article: article from journal or magazin.
Collection
Publications
Title
Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.
Journal
Nature Medicine
Author(s)
Atreya R., Mudter J., Finotto S., Müllberg J., Jostock T., Wirtz S., Schütz M., Bartsch B., Holtmann M., Becker C., Strand D., Czaja J., Schlaak J.F., Lehr H.A., Autschbach F., Schürmann G., Nishimoto N., Yoshizaki K., Ito H., Kishimoto T., Galle P.R., Rose-John S., Neurath M.F.
ISSN
1078-8956 (Print)
ISSN-L
1078-8956
Publication state
Published
Issued date
2000
Volume
6
Number
5
Pages
583-588
Language
english
Abstract
The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.
Keywords
Adult, Animals, Antigens, CD/metabolism, Apoptosis/immunology, Colitis, Ulcerative/immunology, Crohn Disease/immunology, Cytokine Receptor gp130, DNA-Binding Proteins/metabolism, Female, Humans, Interleukin-6/metabolism, Male, Membrane Glycoproteins/metabolism, Mice, Mice, Inbred BALB C, Middle Aged, Models, Immunological, Protein Binding, Proto-Oncogene Proteins c-bcl-2/metabolism, Receptors, Interleukin-6/antagonists & inhibitors, STAT3 Transcription Factor, Signal Transduction, T-Lymphocytes/immunology, Trans-Activators/metabolism, bcl-X Protein
Pubmed
Create date
27/09/2011 13:16
Last modification date
20/08/2019 13:13
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