Nature Medicine
6, 583 - 588 (2000)
doi:10.1038/75068
Blockade of interleukin 6 trans signaling suppresses T-cell resistance
against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease
and experimental colitis in vivoR. Atreya1, 6, J. Mudter1, 6, S. Finotto1, J. Müllberg1, T. Jostock1, S. Wirtz1, M. Schütz1, B. Bartsch1, M. Holtmann1, C. Becker1, D. Strand1, J. Czaja1, J. F. Schlaak1, H.A. Lehr3, F. Autschbach4, G. Schürmann5, N. Nishimoto2, K. Yoshizaki2, H. Ito2, T. Kishimoto2, P.R. Galle1, S. Rose-John1
& M.F. Neurath11
Lab. of Immunology and Section Pathophysiology, I.
Medical Clinic, University of Mainz, 55131 Mainz,
Germany
2
Osaka University, Suita 565-0871
, Japan
3
Institute of Pathology, University of Mainz,
55131 Mainz, Germany
4
Institute of Pathology, University of Heidelberg,
69120 Heidelberg, Germany
5
Department of Surgery, University of Münster,
48129 Münster, Germany
6
R.A. and J.M. contributed equally to this manuscript
Correspondence should be addressed to M.F. Neurath neurath@1-med.klinik.uni-mainz.deThe 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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