Interleukin-8: novel roles in human airway smooth muscle cell contraction and migration.
In patients with cystic fibrosis (CF) and asthma, elevated levels of interleukin-8 (IL-8) are found in the airways. IL-8 is a CXC chemokine that is a chemoattractant for neutrophils through CXCR1 and CXCR2 G protein-coupled receptors. We hypothesized that IL-8 acts directly on airway smooth muscle cells (ASMC) in a way that may contribute to the enhanced airway responsiveness and airway remodeling observed in CF and asthma. The aim of this study was to determine whether human ASMC (HASMC) express functional IL-8 receptors (CXCR1 and CXCR2) linked to cell contraction and migration. Experiments were conducted on cells harvested from human lung specimens. Real-time PCR and fluorescence-activated cell sorting analysis showed that HASMC expressed mRNA and protein for both CXCR1 and CXCR2. Intracellular Ca(2+) concentration ([Ca(2+)](i)) increased from 115 to 170 nM in response to IL-8 (100 nM) and decreased after inhibition of phospholipase C (PLC) with U-73122. On blocking the receptors with specific neutralizing antibodies, changes in [Ca(2+)](i) were abrogated. IL-8 also contracted the HASMC, decreasing the length of cells by 15%, and induced a 2.5-fold increase in migration. These results indicate that HASMC constitutively express functional CXCR1 and CXCR2 that mediate IL-8-triggered Ca(2+) release, contraction, and migration. These data suggest a potential role for IL-8 in causing abnormal airway structure and function in asthma and CF.
Govindaraju
Vasanthi
V
Seymoure Heisler Laboratory of the Montreal Chest Institute Research Center, McGill University, Montreal, Quebec, Canada H2X 2P2.
Michoud
Marie-Claire
MC
Al-Chalabi
Mustafa
M
Ferraro
Pasquale
P
Powell
William S
WS
Martin
James G
JG
D000906:Antibodies / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004963:Estrenes / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors; D016209:Interleukin-8 / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D009500:Neutralization Tests; D010080:Oxazoles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000235:genetics; D012137:Respiratory System / Q000166:cytology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D000906:Antibodies; D004963:Estrenes; D053496:Inositol 1,4,5-Trisphosphate Receptors; D016209:Interleukin-8; D047028:Macrocyclic Compounds; D010080:Oxazoles; D011760:Pyrrolidinones; D012333:RNA, Messenger; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C108644:xestospongin A; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D010738:Type C Phospholipases; D002118:Calcium