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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

Nature Medicine volume 6, pages 583–588 (2000)Cite this article

An Erratum to this article was published on 04 November 2010

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)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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  1. R. Atreya and J. Mudter: R.A. and J.M. contributed equally to this manuscript

Authors and Affiliations

  1. Lab. of Immunology and Section Pathophysiology, I. Medical Clinic, University of Mainz, Mainz, 55131, Germany

    R. Atreya, J. Mudter, S. Finotto, J. Müllberg, T. Jostock, S. Wirtz, M. Schütz, B. Bartsch, M. Holtmann, C. Becker, D. Strand, J. Czaja, J. F. Schlaak, P.R. Galle, S. Rose-John & M.F. Neurath

  2. Osaka University, Suita, 565-0871 , Japan

    N. Nishimoto, K. Yoshizaki, H. Ito & T. Kishimoto

  3. Institute of Pathology, University of Mainz, Mainz, 55131, Germany

    H.A. Lehr

  4. Institute of Pathology, University of Heidelberg, Heidelberg, 69120, Germany

    F. Autschbach

  5. Department of Surgery, University of Münster, Münster, 48129, Germany

    G. Schürmann

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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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