title: 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.
authors.affiliation: Lab. of Immunology and Section Pathophysiology, I. Medical Clinic, University of Mainz, 55131 Mainz, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Atreya
authors.forename: J
authors.initials: J
authors.lastname: Mudter
authors.forename: S
authors.initials: S
authors.lastname: Finotto
authors.forename: J
authors.initials: J
authors.lastname: Müllberg
authors.forename: T
authors.initials: T
authors.lastname: Jostock
authors.forename: S
authors.initials: S
authors.lastname: Wirtz
authors.forename: M
authors.initials: M
authors.lastname: Schütz
authors.forename: B
authors.initials: B
authors.lastname: Bartsch
authors.forename: M
authors.initials: M
authors.lastname: Holtmann
authors.forename: C
authors.initials: C
authors.lastname: Becker
authors.forename: D
authors.initials: D
authors.lastname: Strand
authors.forename: J
authors.initials: J
authors.lastname: Czaja
authors.forename: J F
authors.initials: JF
authors.lastname: Schlaak
authors.forename: H A
authors.initials: HA
authors.lastname: Lehr
authors.forename: F
authors.initials: F
authors.lastname: Autschbach
authors.forename: G
authors.initials: G
authors.lastname: Schürmann
authors.forename: N
authors.initials: N
authors.lastname: Nishimoto
authors.forename: K
authors.initials: K
authors.lastname: Yoshizaki
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: T
authors.initials: T
authors.lastname: Kishimoto
authors.forename: P R
authors.initials: PR
authors.lastname: Galle
authors.forename: S
authors.initials: S
authors.lastname: Rose-John
authors.forename: M F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D003093:Colitis, Ulcerative / Q000276:immunology*; D003424:Crohn Disease / Q000276:immunology*; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D018448:Models, Immunological; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: D015703:Antigens, CD; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D051020:bcl-X Protein; D050822:Cytokine Receptor gp130