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
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.
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Genetic deletion of STAT3 in innate immune cells, such as myeloid cells (neutrophils and macrophages), and enterocytes results in chronic colitis.
“In contrast, genetic deletion of STAT3 in innate immune cells, such as myeloid cells (neutrophils and macrophages), and enterocytes resulted in chronic colitis (Takeda et al., 1999; Atreya et al., 2000; Yamamoto et al., 2000; Suzuki et al., 2001; Pickert et al., 2009).”
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Self-citation
- Authors
- 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.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- University of Münster (DE)
- The University of Osaka (JP)
- Corresponding author
- Neurath, M.F.
- ORCID
- Venue
- Nature Medicine
- Published
- 2000-05
- Volume
- 6
- Issue
- 5
- Pages
- 583-588
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2117521006
- Cited by
- 1,293
- References
- 0
- Citations by year
- 2026: 19 · 2025: 31 · 2024: 39 · 2023: 42 · 2022: 40 · 2021: 53 · 2020: 57 · 2019: 52 · 2018: 51 · 2017: 54 · 2016: 58 · 2015: 54 · 2014: 61 · 2013: 67 · 2012: 36
- FWCI
- 28.76
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-11-04)
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- interleukin-6, soluble IL-6 receptor, IL-6 trans-signaling, T cell apoptosis, Crohn's disease, experimental colitis, lamina propria T cells, T helper type 1 cells, Bcl-2, Bcl-xL, STAT3, chronic intestinal inflammation, anti-inflammatory therapy
- MeSH terms
- Adult, Animals, Colitis, Ulcerative, Crohn Disease, DNA-Binding Proteins, Female, Humans, Male, Membrane Glycoproteins, Mice, Inbred BALB C, Middle Aged, Protein Binding, T-Lymphocytes, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Apoptosis, Models, Immunological, Proto-Oncogene Proteins c-bcl-2, Receptors, Interleukin-6, STAT3 Transcription Factor, Cytokine Receptor gp130, bcl-X Protein, Mice
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