TNF-alpha and IFN-gamma inversely modulate expression of the IL-17E receptor in airway smooth muscle cells.
The interleukin-17B receptor (IL-17BR) is expressed in a variety of tissues and is upregulated under inflammatory conditions. This receptor binds both its cognate ligand IL-17B and IL-17E/IL-25, a novel cytokine known to promote Th2 responses. The present study shows that airway smooth muscle cells express IL-17BR in vitro and that its expression is upregulated by TNF-alpha and downregulated by IFN-gamma. Our data indicate that TNF-alpha upregulates IL-17BR mainly through nuclear factor-kappaB as assessed with the IkappaB kinase 2 inhibitor AS-602868. In addition, both IFN-gamma and dexamethasone are able to antagonize a TNF-alpha-induced IL-17BR increase in mRNA expression. The mitogen-activated protein kinase kinase inhibitor U0126 totally reversed the inhibition observed with IFN-gamma, suggesting the involvement of the extracellular signal-regulated kinase pathway in this effect. In addition, on stimulation with IL-17E, airway smooth muscle cells increase their expression of ECM components, namely procollagen-alphaI and lumican mRNA. Furthermore, immunohistochemical analysis of biopsies from asthmatic subjects reveals that this receptor is abundant in smooth muscle layers. This is the first report showing IL-17BR receptor in structural cells of the airways. Our results suggest a potential proremodeling effect of IL-17E on airway smooth muscle cells through the induction of ECM and that its receptor is upregulated by proinflammatory conditions.
Lajoie-Kadoch
Stéphane
S
Meakins-Christie Laboratories, McGill University, 3626 St-Urbain Street, Montreal, Québec, Canada H2X 2P2.
Joubert
Philippe
P
Létuvé
Séverine
S
Halayko
Andrew J
AJ
Martin
James G
JG
Soussi-Gounni
Abdellilah
A
Hamid
Qutayba
Q
D000818:Animals; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D020381:Interleukin-17 / Q000502:physiology*; D051379:Mice; D009130:Muscle, Smooth / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D018123:Receptors, Interleukin / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012143:Respiratory Physiological Phenomena; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016207:Cytokines; D020381:Interleukin-17; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma