title: Loss of lung WWOX expression causes neutrophilic inflammation.
abstract: The tumor suppressor WW domain-containing oxidoreductase (WWOX) exhibits regulatory interactions with an array of transcription factors and signaling molecules that are positioned at the well-known crossroads between inflammation and cancer. WWOX is also subject to downregulation by genotoxic environmental exposures, making it of potential interest to the study of lung pathobiology. Knockdown of lung WWOX expression in mice was observed to cause neutrophil influx and was accompanied by a corresponding vascular leak and inflammatory cytokine production. In cultured human alveolar epithelial cells, loss of WWOX expression resulted in increased c-Jun- and IL-8-dependent neutrophil chemotaxis toward cell monolayers. WWOX was observed to directly interact with c-Jun in these cells, and its absence resulted in increased nuclear translocation of c-Jun. Finally, inhibition of the c-Jun-activating kinase JNK abrogated the lung neutrophil influx observed during WWOX knockdown in mice. Altogether, these observations represent a novel mechanism of pulmonary neutrophil influx that is highly relevant to the pathobiology and potential treatment of a number of different lung inflammatory conditions.
authors.affiliation: Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois ssingl6@uic.edu.
authors.forename: Sunit
authors.initials: S
authors.lastname: Singla
authors.affiliation: Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Shruthi
authors.initials: S
authors.lastname: Sethuraman
authors.affiliation: Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Sysol
authors.affiliation: Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Amulya
authors.initials: A
authors.lastname: Gampa
authors.affiliation: Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Shuangping
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology*; D010088:Oxidoreductases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D000873:Anthracenes; D016207:Cytokines; D018836:Inflammation Mediators; D016209:Interleukin-8; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; C432165:pyrazolanthrone; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C428130:Wwox protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases
keywords: WWOX; inflammation; lung injury; neutrophils