C-Reactive Protein Downregulates TRAIL Expression in Human Peripheral Monocytes via an Egr-1–Dependent Pathway

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 þ monocytes were exposed to recombinant CRP (1-10 mmol/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 þ 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 þ monocytes also in response to IFN-a, 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.

Serum Soluble Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Levels in Older Subjects with Dementia and Mild Cognitive Impairment

“…In agreement with a previous study [25], uric acid, total cholesterol, and triglycerides were higher in subjects belonging to the III TRAIL tertile. In contrast with a previous report [26], hemoglobin, creatinine, albumin, HDL and LDL cholesterol, fasting glucose and hsCRP were not associated with serum TRAIL levels. Concerning comorbidities, the prevalence of COPD was inversely associated with TRAIL levels, as previously reported [27].…”

Patients with Ankylosing Spondylitis and Low Disease Activity because of Anti-TNF-Alpha Therapy Have Higher TRAIL Levels Than Controls: A Potential Compensatory Effect

“…In line with these results, a marginally positive correlation between TRAIL and apelin, an anti-inflammatory adipokine, was also observed. These results further support the previously described anti-inflammatory role of TRAIL [17]. …”

Soluble TRAIL is present at high concentrations in seminal plasma and promotes spermatozoa survival

“…Although TRAIL/TRAILR system is generally considered to be a component of the cell anti-tumorigenic activity, its physiopathological role is broader than originally thought (Di Pietro & Zauli 2004). In particular, the ability of TRAIL to suppress inflammatory reactions has been demonstrated in a variety of studies (Li et al 2012, Marcuzzi et al 2012, Keuper et al 2013, Secchiero et al 2013, Walczak 2013. The second major finding of our study was that recombinant TRAIL, used at concentrations comparable to those found in seminal plasma (10 ng/ml), significantly increased the overall survival of capacitated spermatozoa.…”

“…In addition, the presence of TRAIL in seminal plasma has never been evaluated. It should also be taken into consideration that a growing number of studies from different groups of investigators have shown that TRAIL displays anti-inflammatory activity (Li et al 2012, Marcuzzi et al 2012, Keuper et al 2013, Secchiero et al 2013, Walczak 2013. On these bases, the aim of our present study was i) to analyze the presence and the levels of soluble TRAIL in the seminal samples and the surface expression of TRAIL receptors in the sperm cellular fraction and ii) to evaluate the potential biological activity of soluble TRAIL, by assessing the in vitro response of spermatozoa in terms of vitality/survival and motility upon exposure to recombinant TRAIL.…”