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Clin Cancer Res. 2013 Apr 15;19(8):1949-59. doi: 10.1158/1078-0432.CCR-12-3027. Epub 2013 Mar 6.

C-Reactive protein downregulates TRAIL expression in human peripheral monocytes via an Egr-1-dependent pathway.

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  • 1AuDepartment of Morphology and Embryology, Laboratorio per le Tecnologie delle Terapie Avanzate Centre, University of Ferrara, Ferrara, Trieste, Italy.

Abstract

PURPOSE:

To investigate the potential link between C-reactive protein (CRP), a known biomarker of acute and chronic inflammation, and TRAIL, a cytokine which plays a key role in the immune-surveillance against tumors.

EXPERIMENTAL DESIGN:

Primary normal peripheral blood mononuclear cell (PBMC) and CD14(+) monocytes were exposed to recombinant CRP (1-10 μmol/L). TRAIL expression was analyzed by ELISA and/or by quantitative real-time PCR (qRT-PCR). In parallel, the potential role of the transcription factor Egr-1 was investigated by analyzing its modulation in response to CRP and by transfection experiments.

RESULTS:

In vitro CRP exposure induced downregulation of TRAIL expression, both at the mRNA and protein level, in unfractionated PBMC and in purified CD14(+) monocytes. TRAIL downregulation was not due to a specific toxicity or to contaminating lipopolysaccharide (LPS), as shown by the lack of induction of monocyte apoptosis and by the inability of the inhibitor of LPS polymyxin B to interfere with CRP activity. Of note, CRP downregulated TRAIL expression/release in CD14(+) monocytes also in response to IFN-α, the most potent inducer of TRAIL. At the molecular level, the downmodulation of TRAIL by CRP was accompanied by a significant increase of Egr-1. Consistently, Egr-1 overexpression reduced the baseline levels of TRAIL mRNA, whereas knocking down Egr-1 counteracted the ability of CRP to downregulate TRAIL.

CONCLUSIONS:

Our findings suggest that a chronic elevation of CRP, which occurs during systemic inflammation and often in patients with cancer, might contribute to promote cancer development and/or progression by downregulating TRAIL in immune cells.

PMID:
23468057
[PubMed - indexed for MEDLINE]
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