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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Minami, M. et al. STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc. Natl. Acad .Sci. USA 93, 3963–3966 (1996).
Peters, M. et al. The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J. Exp. Med. 183, 1399–1406 (1996).
Peters, M. et al. Extramedullary expansion of hematopoietic progenitor cells in IL-6/sIL-6R double transgenic mice. J. Exp. Med. 185 , 755–766 (1997).
Peters, M., Müller, A. & Rose-John, S. Interleukin-6 and soluble interleukin-6 receptor: Direct stimulation of gp130 and hematopoiesis. Blood 92, 3295–3504 (1998).
Romano, M. et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 5, 315 –325 (1997).
Rose-John, S. & Heinrich, P.C. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem. J. 300, 281–290 ( 1994).
Tamura, T. et al. Soluble IL-6 receptor triggers osteoclast formation by IL-6. Proc. Natl. Acad. Sci. USA 90, 11924– 11928 (1993).
Podolsky, D.K. Inflammatory bowel disease. New Engl. J. Med. 325, 928–937 (1991).
Strober, W. & Neurath, M.F in Clinical Immunology (R.R. Rich, editor) 1401–1428 (Mosby, St. Louis, 1995).
Sartor, R. Postoperative recurrence of Crohn's disease: the enemy is within the fecal stream. Gastroenterology 114, 398– 400 (1998).
Boirivant, M. et al. Lamina propria T cells in Crohn's disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis. Gastroenterology 116, 557–565 ( 1999).
Ina, K. et al. Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a bcl-2/bax mucosal imbalance. J. Immunol. 163, 1081–1090 (1999).
Gross, V., Andus, T, Caesar, I., Roth, M. & Schölmerich, J. Evidence for continuous stimulation of IL-6 production in Crohn's disease. Gastroenterology 102, 514–519 (1992).
Reinecker, H. C. et al. Enhanced secretion of tumour necrosis factor-α, IL6 and IL-1β by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin. Exp. Immunol. 94, 174–181 ( 1993).
Catlett-Falcone, R. et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105–115 (1999).
Fukada, T. et al. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5, 449–460 ( 1996).
Teague, T.K., Marrack, P., Kappler, J.W. & Vella, A.T. IL-6 rescues resting mouse T cells from apoptosis. J. Immunol. 158, 5791–5796 ( 1997).
Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 2, 553–562 ( 1994).
Neurath, M.F., Fuss, I., Kelsall, B.L., Stuber, E. & Strober, W. Antibodies to IL-12 abrogate established experimental colitis in mice. J. Exp. Med. 182, 1280– 1289 (1995).
Kühn, R., Löhler, J. Rennick, D. Rajewsky, K. & Müller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).
Targan, S.R. et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. New Engl. J. Med. 337, 1029–1035 ( 1997).
Mullberg, J. et al. A metalloprotease inhibitor blocks shedding of the IL-6 receptor and the p60 TNF receptor. J. Immunol. 155, 5198–5205 (1995).
Mitsuyama, K. et al. Soluble IL-6 receptors in inflammatory bowel disease: relation to circulating IL-6. Gut 36, 45– 49 (1995).
Bouhnik, Y. et al. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurin. Lancet 347, 215–219 (1996).
Jones, S.A. et al. C-reactive Protein: A physiological activator of interleukin 6 receptor shedding. J. Exp. Med. 189, 599 –604 (1999).
Wirtz, S. et al. Cutting Edge: Chronic intestinal inflammation in STAT-4 transgenic mice: Characterization of disease and adoptive transfer by TNF-plus IFN-γ producing CD4+ T cells that respond to bacterial antigens. J. Immunol. 162, 1884–1888 ( 1999).
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.
About this article
Cite this article
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
Cytokine characteristic of cerebrospinal fluid from children with enteroviral meningitis compared to bacterial meningitis
Journal of Clinical Laboratory Analysis (2020)
Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene therapy: A comprehensive review
Autoimmunity Reviews (2020)
Synbiotic supplementation with prebiotic green banana resistant starch and probiotic Bacillus coagulans spores ameliorates gut inflammation in mouse model of inflammatory bowel diseases
European Journal of Nutrition (2020)
Effect of Loureirin B on Crohn’s disease rat model induced by TNBS via IL-6/STAT3/NF-κB signaling pathway
Chinese Medicine (2020)
Red lentil supplementation reduces the severity of dextran sodium sulfate-induced colitis in C57BL/6 male mice
Journal of Functional Foods (2020)