Effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle.
Increased levels of IL-6 are documented in asthma, but its contribution to the pathology is unknown. Asthma is characterized by airway wall thickening due to increased extracellular matrix deposition, inflammation, angiogenesis, and airway smooth muscle (ASM) mass. IL-6 binds to a specific membrane-bound receptor, IL-6 receptor-alpha (mIL-6Ralpha), and subsequently to the signaling protein gp130. Alternatively, IL-6 can bind to soluble IL-6 recpetor-alpha (sIL-6Ralpha) to stimulate membrane receptor-deficient cells, a process called trans-signaling. We discovered that primary human ASM cells do not express mIL-6Ralpha and, therefore, investigated the effect of IL-6 trans-signaling on the pro-remodeling phenotype of ASM. ASM required sIL-6Ralpha to activate signal transducer and activator 3, with no differences observed between cells from asthmatic subjects compared with controls. Further analysis revealed that IL-6 alone or with sIL-6Ralpha did not induce release of matrix-stimulating factors (including connective tissue growth factor, fibronectin, or integrins) and had no effect on mast cell adhesion to ASM or ASM proliferation. However, in the presence of sIL-6Ralpha, IL-6 increased eotaxin and VEGF release and may thereby contribute to local inflammation and vessel expansion in airway walls of asthmatic subjects. As levels of sIL-6Ralpha are increased in asthma, this demonstration of IL-6 trans-signaling in ASM has relevance to the development of airway remodeling.
Ammit
Alaina J
AJ
Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. ajammit@pharm.usyd.edu.au
Moir
Lyn M
LM
Oliver
Brian G
BG
Hughes
J Margaret
JM
Alkhouri
Hatem
H
Ge
Qi
Q
Burgess
Janette K
JK
Black
Judith L
JL
Roth
Michael
M
D001249:Asthma / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins