IL-17R activation of human airway smooth muscle cells induces CXCL-8 production via a transcriptional-dependent mechanism.
Airway neutrophilia has been recognized as a predominant feature of acute lung disorders. While it has been shown that IL-17 induces expression of the CXC chemokines in the airways leading to neutrophil recruitment, the IL-17R expression in human ASM cells and the molecular mechanism by which IL-17 mediates neutrophilic chemo-attractant CXCL-8 (IL-8) production have not been determined. Our study showed that ASM cells express steady state IL-17R protein, mRNA and surface-bound receptor. Interestingly, airway sections from COPD patients revealed IL-17R-positive immunostaining within ASM bundles. IL-17 was capable of stimulating CXCL-8 protein release from ASM cells which was significantly decreased by neutralizing anti-IL-17 mAb. Furthermore, IL-17 induction of CXCL-8 mRNA and protein release from ASM cells was abrogated by transcriptional inhibitor actinomycin D. CXCL-8 promoter reporter analysis using wild type and site specific mutant constructs demonstrated a key role for AP1 and NF-kappaB binding sites in IL-17-induced CXCL-8 expression. These data demonstrate that IL-17 mediates CXCL-8 expression in ASM cells via a transcriptional mechanism depending on NF-kappaB and AP-1 pathways. Together, our findings suggest that ASM cells play an important role in airway neutrophilia.
Rahman
M S
MS
Department of Immunology, University of Manitoba, BMSB, Faculty of Medicine, 730, William Avenue, Winnipeg, MB, Canada R3E0W3.
Yang
Jie
J
Shan
Lian Yu
LY
Unruh
Helmut
H
Yang
Xi
X
Halayko
Andrew J
AJ
Gounni
Abdelilah Soussi
AS
D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000276:immunology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D053722:Receptors, Interleukin-17; D012137:Respiratory System / Q000276:immunology*; D014132:Trachea / Q000166:cytology; D015533:Transcriptional Activation
C109985:IL17RA protein, human; D020381:Interleukin-17; D016209:Interleukin-8; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17