Stretch-induced IL-8 depends on c-Jun NH2-terminal and nuclear factor-kappaB-inducing kinases.
Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including interleukin (IL)-8. The mechanisms regulating lung stretch-induced cytokine production are unclear. We hypothesized that stretch-induced IL-8 production is dependent on the activation of the mitogen-activated protein kinases, c-Jun NH2-terminal kinases (JNK), p38, and/or extracellular signal-regulated kinase (ERK) 1/2. We exposed A549 cells, a type II-like alveolar epithelial cell line, to cyclic stretch at 20 cycles/min for 5 min-2 h. Cyclic stretch induced IL-8 protein production, IL-8 mRNA expression, and JNK activation, but only transient activation of p38 and ERK1/2. Inhibition of stretch-induced JNK activation by adenovirus-mediated gene transfer of stress-activated protein kinase (SEK-1), a dominant-negative mutant of SEK-1, the immediate upstream activator of the JNKs, and pharmacological JNK inhibitor II SP-600125 blocked IL-8 mRNA expression and attenuated IL-8 production. Inhibition of p38 and ERK1/2 did not affect stretch-induced IL-8 production. Stretch-induced activation NF-kappaB and activator protein (AP)-1 was blocked by NF-kappaB inhibitor and JNK inhibitor, respectively. An NF-IL-6 site was not essential for cyclic stretch-induced IL-8 promoter activity. Stretch also induced NF-kappaB-inducing kinase (NIK) activation, and inhibition of NF-kappaB attenuated IL-8 mRNA expression and IL-8 production. We conclude that stretch-induced transcriptional regulation of IL-8 mRNA and IL-8 production was via activation of AP-1 and NF-kappaB and was dependent on JNK and NIK activation, respectively.
Li
Li-Fu
LF
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Ouyang
Bin
B
Choukroun
Gabriel
G
Matyal
Robina
R
Mascarenhas
Marcella
M
Jafari
Behrouz
B
Bonventre
Joseph V
JV
Force
Thomas
T
Quinn
Deborah A
DA
D000873:Anthracenes / Q000494:pharmacology; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013314:Stress, Mechanical; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D000873:Anthracenes; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase