Noncanonical NF-κB mediates the Suppressive Effect of Neutrophil Elastase on IL-8/CXCL8 by Inducing NKRF in Human Airway Smooth Muscle.
Neutrophil elastase (NE) suppresses IL-8/CXCL8 in human airway smooth muscle cells (hASM) while stimulating its production in respiratory epithelial cells. This differential effect is mediated by the selective induction of NKRF and dysregulation in chronic inflammatory diseases. We hypothesized that the differential activation of NF-κB subunits confer the opposite effect of NKRF on IL-8/CXCL8 in primary hASM and A549 cells stimulated with NE. The events occurring at the promoters of NKRF and IL-8/CXCL8 were observed by ChIP assays, and the functional role of RelB was confirmed by knockdown and overexpression. Although p65 was stimulated in both cell types, RelB was only activated in NE-treated hASM, as confirmed by NF-κB DNA binding ELISA, Western blotting and confocal microscopy. Knockdown of RelB abolished the induction of NKRF and converted the suppression of IL-8/CXCL8 to stimulation. The forced expression of RelB induced NKRF production in hASM and A549 cells. NE activated the NIK/IKK1/RelB non-canonical NF-κB pathway in hASM but not in A549. The nuclear-translocated RelB was recruited to the NKRF promoter around the putative κB site, accompanied by p52 and RNA polymerase II. In conclusion, NFRF is a novel RelB-response gene, and NE is a stimulator of the non-canonical RelB/NF-κB pathway in hASM.
School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Shu-Chuan
SC
Ho
Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Sheng-Ming
SM
Wu
Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.|Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Po-Hao
PH
Feng
Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.|Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Wen-Te
WT
Liu
Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Kuan-Yuan
KY
Chen
School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.|Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Hsiao-Chi
HC
Chuang
Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang-Gung Memorial Hospital, Taoyuan, Taiwan.
Yao-Fei
YF
Chan
Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Lu-Wei
LW
Kuo
Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.|Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Kang-Yun
KY
Lee
D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012137:Respiratory System / Q000166:cytology* / Q000378:metabolism*
D016209:Interleukin-8; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C111027:NKRF protein, human; D012097:Repressor Proteins; D019272:Leukocyte Elastase