Atrial natriuretic peptide down-regulates LPS/ATP-mediated IL-1β release by inhibiting NF-kB, NLRP3 inflammasome and caspase-1 activation in THP-1 cells

Abstract

Atrial natriuretic peptide (ANP) is an hormone/paracrine/autocrine factor regulating cardiovascular homeostasis by guanylyl cyclase natriuretic peptide receptor (NPR-1). ANP plays an important role also in regulating inflammatory and immune systems by altering macrophages functions and cytokines secretion. Interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine involved in a wide range of biological responses, including the immunological one. Unlike other cytokines, IL-1β production is rigorously controlled. Primarily, NF-kB activation is required to produce pro-IL-1β; subsequently, NALP3 inflammasome/caspase-1 activation is required to cleave pro-IL-1β into the active secreted protein. NALP3 is a molecular platform capable of sensing a large variety of signals and a major player in innate immune defense. Due to their pleiotropism, IL-1β and NALP3 dysregulation is a common feature of a wide range of diseases. Therefore, identifying molecules regulating IL-1β/NALP3/caspase-1 expression is an important step in the development of new potential therapeutic agents. The aim of our study was to evaluate the effect of ANP on IL-1β/NALP3/caspase-1 expression in LPS/ATP-stimulated human THP1 monocytes. We provided new evidence of the direct involvement of ANP/NPR-1/cGMP axis on NF-kB/NALP3/caspase-1-mediated IL-1β release and NF-kB-mediated pro-IL-1β production. In particular, ANP inhibited both NF-kB and NALP3/caspase-1 activation leading to pro- and mature IL-1β down-regulation. Our data, pointing out a modulatory role of this endogenous peptide on IL-1β release and on NF-kB/NALP3/caspase-1 activation, indicate an important anti-inflammatory and immunomodulatory effect of ANP via these mechanisms. We suggest a possible employment of ANP for the treatment of inflammatory/immune-related diseases and IL-1β/NALP3-associated disorders, affecting millions of people worldwide.

A Novel Role for Brain Natriuretic Peptide: Inhibition of IL-1βSecretion via Downregulation of NF-kB/Erk 1/2 and NALP3/ASC/Caspase-1 Activation in Human THP-1 Monocyte

“…Concomitantly, the here found BNP inhibition of IL-1 release might contribute also to balance and/or restore BNP secretion itself, by an autocrine/paracrine loop. In support, NPR-1 is expressed on human monocytes [35,38], macrophages [44], monocyte-derived dendritic cells [45], and peripheral blood mononuclear cells [35]. In agreement, here we newly report that THP-1 cells respond to BNP with an increase in cGMP production, thus indicating NPR-1 activation.…”

“…In addition, the main cytokines released during inflammation increase BNP production and secretion in vitro [37,40,41] and in many conditions where IL-1 and other cytokines levels are increased [42], BNP plasma levels may be particularly elevated [43]. Finally, BNP inhibits monocytes chemotaxis [35] and influences some inflammatory mediators production in macrophages [36] and NPR-1 is expressed on immune cells [30,35,38,44,45]. Altogether, these observations suggest a role for BNP in inflammation and its possible immunomodulatory action.…”

“…NPR-1 activation induces an increase of cGMP intracellular levels, leading to the activation of specific cGMP-dependent protein kinases, phosphodiesterases and cyclic nucleotide gated cation channels [30,31,34]. NPs and NPR-1 are expressed in many tissues and exert endocrine, autocrine, and paracrine effects in normal or pathological conditions [30,31,34] and a wide range of further activities, including an emerging role on inflammation and immunity [30,31,[35][36][37][38]. In particular, BNP plasma level is upregulated in patients during inflammatory contexts, such as sepsis or septic shock [37,39] and in several inflammatory diseases with or without cardiac dysfunction [37].…”

Sp1 mediates phorbol ester (PMA)-induced expression of membrane-bound guanylyl cyclase GC-A in human monocytic cells*

“…Here, by applying qPCR, Western blotting, and ELISA ( Fig. 1), we found that the active form of GC-A receptor was produced in PMA-differentiated macrophagelike cells, but not in undifferentiated monocytic THP-1 cells, although few literature reports show the presence of GC-A in these cells (Glezeva et al, 2013;Mezzasoma et al, 2016). It is well known that activation of PKC by PMA triggers activation of the MEK/ERK-signaling cassette involved in transduction of extracellular stimuli to molecular networks responsible for differentiation and other cellular processes (Dieter & Schwende, 2000;Miranda et al, 2002).…”

“…Reports demonstrate anti-inflammatory action of this enzyme. It was found that the ANP-triggered GC-A/ cGMP-signaling pathway decreases activity of AP-1 and NF-κB transcription factors in activated myeloid cells and thus suppresses release of inflammatory cytokines (IL-1β, IL-6, TNFα) and inhibits expression of inducible nitric oxide synthase (Kiemer et al, 2000;Mitkiewicz et al, 2011;Mezzasoma et al, 2016). The anti-inflammatory action of ANP was shown to also occur in mice treated with LPS (Ladetzki-Baehs et al, 2007;Nojiri et al, 2014).…”