Loss of lung WWOX expression causes neutrophilic inflammation

Sunit Singla, Jiwang Chen, Shruthi Sethuraman, Justin R. Sysol, Amulya Gampa, Shuangping Zhao, Roberto Machado

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)L903-L911
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume312
Issue number6
DOIs
StatePublished - Jun 5 2017
Externally publishedYes

Fingerprint

Inflammation
Neutrophils
Lung
MAP Kinase Kinase 4
Alveolar Epithelial Cells
Environmental Exposure
Chemotaxis
Interleukin-8
Blood Vessels
Neoplasms
Oxidoreductases
Transcription Factors
Down-Regulation
Cytokines
Therapeutics

Keywords

  • Inflammation
  • Lung injury
  • Neutrophils
  • WWOX

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Loss of lung WWOX expression causes neutrophilic inflammation. / Singla, Sunit; Chen, Jiwang; Sethuraman, Shruthi; Sysol, Justin R.; Gampa, Amulya; Zhao, Shuangping; Machado, Roberto.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 312, No. 6, 05.06.2017, p. L903-L911.

Research output: Contribution to journalArticle

Singla, Sunit ; Chen, Jiwang ; Sethuraman, Shruthi ; Sysol, Justin R. ; Gampa, Amulya ; Zhao, Shuangping ; Machado, Roberto. / Loss of lung WWOX expression causes neutrophilic inflammation. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2017 ; Vol. 312, No. 6. pp. L903-L911.
@article{9e81080de34a4b02a85e85d25420f18e,
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.",
keywords = "Inflammation, Lung injury, Neutrophils, WWOX",
author = "Sunit Singla and Jiwang Chen and Shruthi Sethuraman and Sysol, {Justin R.} and Amulya Gampa and Shuangping Zhao and Roberto Machado",
year = "2017",
month = "6",
day = "5",
doi = "10.1152/ajplung.00034.2017",
language = "English (US)",
volume = "312",
pages = "L903--L911",
journal = "American Journal of Physiology",
issn = "1040-0605",
publisher = "American Physiological Society",
number = "6",

}

TY - JOUR

T1 - Loss of lung WWOX expression causes neutrophilic inflammation

AU - Singla, Sunit

AU - Chen, Jiwang

AU - Sethuraman, Shruthi

AU - Sysol, Justin R.

AU - Gampa, Amulya

AU - Zhao, Shuangping

AU - Machado, Roberto

PY - 2017/6/5

Y1 - 2017/6/5

N2 - 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.

AB - 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.

KW - Inflammation

KW - Lung injury

KW - Neutrophils

KW - WWOX

UR - http://www.scopus.com/inward/record.url?scp=85020296048&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020296048&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00034.2017

DO - 10.1152/ajplung.00034.2017

M3 - Article

VL - 312

SP - L903-L911

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 1040-0605

IS - 6

ER -