The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo.
The cytokine IL-6 acts via a specific receptor complex that consists of the membrane-bound IL-6 receptor (mIL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). In this study, we investigated the role of IL-6R components in asthma. We observed increased levels of sIL-6R in the airways of patients with allergic asthma as compared to those in controls. In addition, local blockade of the sIL-6R in a murine model of late-phase asthma after OVA sensitization by gp130-fraction constant led to suppression of Th2 cells in the lung. By contrast, blockade of mIL-6R induced local expansion of Foxp3-positive CD4+CD25+ Tregs with increased immunosuppressive capacities. CD4+CD25+ but not CD4+CD25- lung T cells selectively expressed the IL-6R alpha chain and showed IL-6-dependent STAT-3 phosphorylation. Finally, in an in vivo transfer model of asthma in immunodeficient Rag1 mice, CD4+CD25+ T cells isolated from anti-IL-6R antibody-treated mice exhibited marked immunosuppressive and antiinflammatory functions. IL-6 signaling therefore controls the balance between effector cells and Tregs in the lung by means of different receptor components. Furthermore, inhibition of IL-6 signaling emerges as a novel molecular approach for the treatment of allergic asthma.
Doganci
Aysefa
A
Laboratory of Cellular and Molecular Immunology of the Lung, First Medical Clinic, University of Mainz, Mainz, Germany.
Eigenbrod
Tatjana
T
Krug
Norbert
N
De Sanctis
George T
GT
Hausding
Michael
M
Erpenbeck
Veit J
VJ
Haddad
El-Bdaoui
el-B
Lehr
Hans A
HA
Schmitt
Edgar
E
Bopp
Tobias
T
Kallen
Karl-J
KJ
Herz
Udo
U
Schmitt
Steffen
S
Luft
Cornelia
C
Hecht
Olaf
O
Hohlfeld
Jens M
JM
Ito
Hiroaki
H
Nishimoto
Norihiro
N
Yoshizaki
Kazuyuki
K
Kishimoto
Tadamitsu
T
Rose-John
Stefan
S
Renz
Harald
H
Neurath
Markus F
MF
Galle
Peter R
PR
Finotto
Susetta
S
D000328:Adult; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000378:metabolism; D018121:Receptors, Cytokine / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D015534:Trans-Activators / Q000276:immunology
D000906:Antibodies; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D018121:Receptors, Cytokine; D015375:Receptors, Interleukin-2; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C456339:cytokine receptor, GLM-R; C064658:RAG-1 protein; D010047:Ovalbumin