A Novel Role for Brain Natriuretic Peptide: Inhibition of IL-1β Secretion via Downregulation of NF-kB/Erk 1/2 and NALP3/ASC/Caspase-1 Activation in Human THP-1 Monocyte.
Interleukin-1β(IL-1β) is a pleiotropic cytokine and a crucial mediator of inflammatory and immune responses. IL-1βprocessing and release are tightly controlled by complex pathways such as NF-kB/ERK1/2, to produce pro-IL-1β, and NALP3/ASC/Caspase-1 inflammasome, to produce the active secreted protein. Dysregulation of both IL-1βand its related pathways is involved in inflammatory/autoimmune disorders and in a wide range of other diseases. Identifying molecules modulating their expression is a crucial need to develop new therapeutic agents. IL-1βis a strong regulator of Brain Natriuretic Peptide (BNP), a hormone involved in cardiovascular homeostasis by guanylyl cyclase Natriuretic Peptide Receptor (NPR-1). An emerging role of BNP in inflammation and immunity, although proposed, remains largely unexplored. Here, we newly demonstrated that, in human THP-1 monocytes, LPS/ATP-induced IL-1βsecretion is strongly inhibited by BNP/NPR-1/cGMP axis at all the molecular mechanisms that tightly control its production and release, NF-kB, ERK 1/2, and all the elements of NALP3/ASC/Caspase-1 inflammasome cascade, and that NALP3 inflammasome inhibition is directly related to BNP deregulatory effect on NF-kB/ERK 1/2 activation. Our findings reveal a novel potent anti-inflammatory and immunomodulatory role for BNP and open new alleys of investigation for a possible employment of this endogenous agent in the treatment of inflammatory/immune-related and IL-1β/NF-kB/ERK1/2/NALP3/ASC/Caspase-1-associated diseases.
Department of Experimental Medicine, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy.
Letizia
0000-0002-6159-0927
L
Mezzasoma
Department of Experimental Medicine, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy.
Cinzia
C
Antognelli
Department of Experimental Medicine, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy.
Vincenzo Nicola
VN
Talesa
D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002470:Cell Survival; D015536:Down-Regulation; D004789:Enzyme Activation; D006706:Homeostasis; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*
D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D020097:Natriuretic Peptide, Brain; D020170:Caspase 1