title: 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.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale L. Severi 1, 06129, Perugia, Italy. letizia.mezzasoma@unipg.it.
authors.forename: Letizia
authors.initials: L
authors.lastname: Mezzasoma
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale L. Severi 1, 06129, Perugia, Italy. cinzia.antognelli@unipg.it.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Antognelli
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale L. Severi 1, 06129, Perugia, Italy. vincenzo.talesa@unipg.it.
authors.forename: Vincenzo Nicola
authors.initials: VN
authors.lastname: Talesa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D009000:Monocytes / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009320:Atrial Natriuretic Factor; D000255:Adenosine Triphosphate; D020170:Caspase 1
keywords: Atrial natriuretic peptide; Caspase-1; Interleukin-1β; NALP3 inflammasome; Nuclear factor-kB; THP1 cells