Article: article from journal or magazin.
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.
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.
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
Last modification date