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.
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.
Atreya
R
R
Lab. of Immunology and Section Pathophysiology, I. Medical Clinic, University of Mainz, 55131 Mainz, Germany.
Mudter
J
J
Finotto
S
S
Müllberg
J
J
Jostock
T
T
Wirtz
S
S
Schütz
M
M
Bartsch
B
B
Holtmann
M
M
Becker
C
C
Strand
D
D
Czaja
J
J
Schlaak
J F
JF
Lehr
H A
HA
Autschbach
F
F
Schürmann
G
G
Nishimoto
N
N
Yoshizaki
K
K
Ito
H
H
Kishimoto
T
T
Galle
P R
PR
Rose-John
S
S
Neurath
M F
MF
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
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