Macrophage migration inhibitory factor governs endothelial cell sensitivity to LPS-induced apoptosis

Rachel L. Damico, Alan Chesley, Laura Johnston, Eric P. Bind, Eric Amaro, Julie Nijmeh, Bedri Karakas, Laura Welsh, David B. Pearse, Joe G.N. Garcia, Michael T. Crow

Research output: Contribution to journalArticlepeer-review

Abstract

Human endothelial cells (EC) are typically resistant to the apoptotic effects of stimuli associated with lung disease. The determinants of this resistance remain incompletely understood. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by human pulmonary artery EC (HPAEC). Its expression increases in response to various death-inducing stimuli, including lipopolysaccharide (LPS). We show here that silencing MIF expression by RNA interference (MIF siRNA) dramatically reduces MIF mRNA expression and the LPS-induced increase in MIF protein levels, thereby sensitizing HPAECs to LPS-induced cell death. Addition of recombinant human MIF (rhMIF) protein prevents the death-sensitizing effect of MIF siRNA. A common mediator of apoptosis resistance in ECs is the death effector domain (DED)-containing protein, FLIP (FLICE-like inhibitory protein). We show that LPS induces a transcription-independent increase in the short isoform of FLIP (FLIPs). This increase is blocked by MIF siRNA but restored with the addition of recombinant MIF protein (rHMIF). While FLIPs siRNA also sensitizes HPAECs to LPS-induced death, the addition of rhMIF does not affect this sensitization, placing MIF upstream of FLIPs in preventing HPAEC death. These studies demonstrate that MIF is an endogenous pro-survival factor in HPAECs and identify a novel mechanism for its role in apoptosis resistance through the regulation of FLIPs. These results show that MIF can protect vascular endothelial cells from inflammation-associated cell damage.

Original languageEnglish (US)
Pages (from-to)77-85
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume39
Issue number1
DOIs
StatePublished - Jul 1 2008

Keywords

  • Apoptosis
  • Endothelial cells
  • FLICE-like inhibitory protein
  • Macrophage migration inhibitory factor

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Macrophage migration inhibitory factor governs endothelial cell sensitivity to LPS-induced apoptosis'. Together they form a unique fingerprint.

Cite this