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

  • An Erratum to this article was published on 01 November 2010

Abstract

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 15) 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)5,6,7. 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 tract8,9,10,11,12. 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.

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Figure 1: Cytokine production and expression of membrane-bound IL-6R in LPMCs.
Figure 2: a, Top row, EMSA using nuclear extracts of purified lamina propria T cells (CD, n = 6; UC, n = 3; control, n = 4) and a radiolabeled STAT-3 consensus DNA binding site, showing the location of the STAT-3 signal (arrow).
Figure 3: Blockade of IL6R or sIL-6R attenuates experimental colitis.
Figure 4: Induction of cell apoptosis upon blockade of the IL-6/sIL-6R system.

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Acknowledgements

The authors thank F. Solem and K.-J. Kallen (First Medical Clinic, University of Mainz, Germany) for their help with the bioassay for sIL-6R. The research of M. F. N., P. R. G., F.A. and S. R.-J. was supported by grants from the Innovationsstiftung Rheinland-Pfalz, the SFBs 413/458/490/405 and the Deutsche Forschungsgemeinschaft.

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Correspondence to M.F. Neurath.

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Atreya, R., Mudter, J., Finotto, S. et al. 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. Nat Med 6, 583–588 (2000). https://doi.org/10.1038/75068

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