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

Paola Secchiero, Erika Rimondi, Maria Grazia Di Iasio, Chiara Agnoletto, Elisabetta Melloni, Ilaria Volpi, Giorgio Zauli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1949-1959
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number8
DOIs
Publication statusPublished - Apr 15 2013

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Secchiero, P., Rimondi, E., Di Iasio, M. G., Agnoletto, C., Melloni, E., Volpi, I., & Zauli, G. (2013). C-reactive protein downregulates TRAIL expression in human peripheral monocytes via an Egr-1-dependent pathway. Clinical Cancer Research, 19(8), 1949-1959. https://doi.org/10.1158/1078-0432.CCR-12-3027