C reactive protein down-regulates TNF-related apoptosis inducing ligand expression in human peripheral monocytes via an Egr-1 dependent pathway.

PURPOSE: To investigate the potential link between C reactive protein (CRP), a known biomarker of acute and chronic inflammation, and TNF-related apoptosis-inducing ligand (TRAIL), a cytokine which plays a key role in the immune-surveillance against tumors. EXPERIMENTAL DESIGN: Primary normal PBMC and CD14+ monocytes were exposed to recombinant CRP (1-10 μM). TRAIL expression was analyzed by ELISA and/or by quantitative RT-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 down-regulation of TRAIL expression, both at the mRNA and protein level, in unfractionated PBMC and in purified CD14+ monocytes. TRAIL down-regulation was not due to aspecific toxicity or to contaminating lipopolysaccharide (LPS), as demonstrated 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 down-regulated TRAIL expression/release in CD14+ monocytes also in response to interferon-α, the most potent inducer of TRAIL. At the molecular level, the down-modulation of TRAIL by CRP was accompanied by a significant increase of Egr-1. Consistently, Egr-1 over-expression reduced the baseline levels of TRAIL mRNA, while knocking-down Egr-1 counteracted the ability of CRP to down-regulate TRAIL. CONCLUSIONS: Our findings suggest that a chronic elevation of CRP, which occurs during systemic inflammation and often in cancer patients, might contribute to promote cancer development and/or progression by down-regulating TRAIL in immune cells.