IL-1β and related cascade are being regarded as suitable targets for a large variety of diseases. Recently, we demonstrated a novel anti-inflammatory/immune-modulatory role for Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP), hormone/paracrine/autocrine factors exerting their biological functions by guanylyl-cyclase Natriuretic Peptide Receptor-1 (NPR-1). Indeed, we showed that they inhibit the NF-kB and ERK 1/2 pathways thus downregulating NALP3-inflammasome cascade activation and related LPS/ATP-induced IL-1β secretion in THP-1 monocytes. The aim of this study was to further investigate the signaling mechanisms involved in ANP/BNP-dependent anti-inflammatory/immune-modulatory effect. cGMP cascade is the key event leading to ANP/BNP cellular and physiological responses mainly via cGMP-dependent protein kinase I (PKG-I) activation. We showed that 8-Br-cGMP, a permeable analogue of cGMP, mimic the ANP/BNP effects, by inhibiting LPS+ATP-induced IL-1β secretion in THP-1 monocytes and interfering on the molecular mechanisms that preside both pro-IL-1β synthesis and release. Likewise, by using KT-5823, a selective PKG-I inhibitor, we demonstrated the direct involvement of PKG-I in ANP/BNP/8-Br-cGMP-related IL-1β/NALP3-inflammasome inhibition via NF-kB pathway de-regulation. All together our data strongly suggest that ANP and BNP exert their anti-inflammatory/immune-modulatory molecular cascade via NPR- 1/cGMP/PKG-I pathway activation. Pharmacological modulation of cGMP pathway is a potential target for a large variety of diseases. Therefore small molecules that can increase cGMP levels are regarded as compounds that can be used in several pathological conditions. Thus, we propose that ANP and BNP, already used in the treatment of heart failure, are of interest also in the treatment of IL-1β/NF-kB/ERK1/2/NALP3/ASC/caspase-1-associated diseases.

Natriuretic peptides: novel insights into the molecular mechanisms of IL-1β and NF-kB/Erk 1/2/NALP3-inflammasome cascade inhibition

Letizia Mezzasoma;Vincenzo Nicola Talesa
2018

Abstract

IL-1β and related cascade are being regarded as suitable targets for a large variety of diseases. Recently, we demonstrated a novel anti-inflammatory/immune-modulatory role for Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP), hormone/paracrine/autocrine factors exerting their biological functions by guanylyl-cyclase Natriuretic Peptide Receptor-1 (NPR-1). Indeed, we showed that they inhibit the NF-kB and ERK 1/2 pathways thus downregulating NALP3-inflammasome cascade activation and related LPS/ATP-induced IL-1β secretion in THP-1 monocytes. The aim of this study was to further investigate the signaling mechanisms involved in ANP/BNP-dependent anti-inflammatory/immune-modulatory effect. cGMP cascade is the key event leading to ANP/BNP cellular and physiological responses mainly via cGMP-dependent protein kinase I (PKG-I) activation. We showed that 8-Br-cGMP, a permeable analogue of cGMP, mimic the ANP/BNP effects, by inhibiting LPS+ATP-induced IL-1β secretion in THP-1 monocytes and interfering on the molecular mechanisms that preside both pro-IL-1β synthesis and release. Likewise, by using KT-5823, a selective PKG-I inhibitor, we demonstrated the direct involvement of PKG-I in ANP/BNP/8-Br-cGMP-related IL-1β/NALP3-inflammasome inhibition via NF-kB pathway de-regulation. All together our data strongly suggest that ANP and BNP exert their anti-inflammatory/immune-modulatory molecular cascade via NPR- 1/cGMP/PKG-I pathway activation. Pharmacological modulation of cGMP pathway is a potential target for a large variety of diseases. Therefore small molecules that can increase cGMP levels are regarded as compounds that can be used in several pathological conditions. Thus, we propose that ANP and BNP, already used in the treatment of heart failure, are of interest also in the treatment of IL-1β/NF-kB/ERK1/2/NALP3/ASC/caspase-1-associated diseases.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11391/1463465
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