Cigarette smoke-induced CXCR3 receptor up-regulation mediates endothelial apoptosis

Linden A. Green, Daniela Petrusca, Raja Shekhar Gangaraju, Tom Gianaris, Kelly S. Schweitzer, Liang Wang, Matthew J. Justice, Irina Petrache, Matthias Clauss

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Endothelial monocyte-activating polypeptide II (EMAP II) and interferon-inducible protein (IP)-10 are proinflammatory mediators, which in addition to their chemokine activities, selectively induce apoptosis in endothelial cells and are up-regulated in the lungs of cigarette smoke-exposed humans. Previously, we showed that EMAP II is an essential mediator of cigarette smoke-induced lung emphysema in mice linking endothelial cell apoptosis with inflammation. Here we addressed the role of the CXCR3 receptor in EMAP II-induced and IP-10-induced apoptosis in endothelial cells and its regulation by cigarette smoke. We found that both neutralizing antibodies and small inhibitory RNA to CXCR3 abrogated EMAP II-induced and IP-10-induced endothelial caspase-3 activation and DNA fragmentation. CXCR3 receptor surface expression in human lung microvascular endothelial cells and in lung tissue endothelium was up-regulated by exposure to cigarette smoke. In tissue culture conditions, EMAP II-induced and IP-10-induced apoptosis was enhanced by preincubation with cigarette smoke extract. Interestingly, serum starvation also induced CXCR3 up-regulation and enhanced EMAP II-induced endothelial apoptosis. Signal transduction via p38 mitogen-activated protein kinase activation was essential for CXCR3-induced cell death, but not for CXCR3 receptor up-regulation by cigarette smoke. In turn, protein nitration was required for CXCR3 receptor up-regulation by cigarette smoke and consequently for subsequent CXCR3-induced cell death. In conclusion, the concerted up-regulation of proinflammatory EMAP II, IP-10, and CXCR3 by cigarette smoke could sustain a cascade of cell death that may promote the alveolar tissue loss noted in human emphysema.

Original languageEnglish (US)
Pages (from-to)807-814
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume47
Issue number6
DOIs
StatePublished - Dec 1 2012

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CXCR3 Receptors
Smoke
Tobacco Products
Up-Regulation
Apoptosis
Endothelial cells
Cell death
Endothelial Cells
Lung
Cell Death
Emphysema
Proteins
Chemical activation
Chemokine CXCL10
Tissue
Nitration
Tissue culture
Signal transduction
p38 Mitogen-Activated Protein Kinases
DNA Fragmentation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Cigarette smoke-induced CXCR3 receptor up-regulation mediates endothelial apoptosis. / Green, Linden A.; Petrusca, Daniela; Gangaraju, Raja Shekhar; Gianaris, Tom; Schweitzer, Kelly S.; Wang, Liang; Justice, Matthew J.; Petrache, Irina; Clauss, Matthias.

In: American journal of respiratory cell and molecular biology, Vol. 47, No. 6, 01.12.2012, p. 807-814.

Research output: Contribution to journalArticle

Green, LA, Petrusca, D, Gangaraju, RS, Gianaris, T, Schweitzer, KS, Wang, L, Justice, MJ, Petrache, I & Clauss, M 2012, 'Cigarette smoke-induced CXCR3 receptor up-regulation mediates endothelial apoptosis', American journal of respiratory cell and molecular biology, vol. 47, no. 6, pp. 807-814. https://doi.org/10.1165/rcmb.2012-0132OC
Green, Linden A. ; Petrusca, Daniela ; Gangaraju, Raja Shekhar ; Gianaris, Tom ; Schweitzer, Kelly S. ; Wang, Liang ; Justice, Matthew J. ; Petrache, Irina ; Clauss, Matthias. / Cigarette smoke-induced CXCR3 receptor up-regulation mediates endothelial apoptosis. In: American journal of respiratory cell and molecular biology. 2012 ; Vol. 47, No. 6. pp. 807-814.
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