Pathological concentrations of homocysteine increases IL-1β production in macrophages in a P2X7, NF-ĸB, and erk-dependent manner.
Elevated plasma levels of homocysteine (Hcy) are associated with the development of coronary artery disease (CAD), peripheral vascular disease, and atherosclerosis. Hyperhomocysteinemia is likely related to the enhanced production of pro-inflammatory cytokines including IL-1β. However, the mechanisms underlying the effects of Hcy in immune cells are not completely understood. Recent studies have established a link between macrophage accumulation, cytokine IL-1β, and the advance of vascular diseases. The purpose of the present study is to investigate the effects of Hcy on IL-1β secretion by murine macrophages. Hcy (100 μM) increases IL-1β synthesis via enhancement of P2X7 expression and NF-ĸB and ERK activation in murine macrophages. In addition, the antioxidant agent N-acetylcysteine (NAC) reduces NF-κB activation, ERK phosphorylation, and IL-1β production in Hcy-exposed macrophages, indicating the importance of ROS in this pro-inflammatory process. In summary, our results show that Hcy may be involved in the synthesis and secretion of IL-1β via NF-ĸB, ERK, and P2X7 stimulation in murine macrophages.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul - UFRGS, 2600-anexo, CEP 90035-003, Porto Alegre, RS, Brazil. rafaelzaninn@gmail.com.|Faculdades de Farmácia, Programa de Pós-Graduação em Biologia Celular e Molecular e Instituto de Toxicologia e Farmacologia, Pontificia Universidade Católica do Rio Grande do Sul - PUCRS, Porto Alegre, RS, Brazil. rafaelzaninn@gmail.com.|Mestrado em Saúde e Desenvolvimento Humano do Unilasalle, Canoas, RS, Brazil. rafaelzaninn@gmail.com.
Rafael Fernandes
RF
Zanin
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul - UFRGS, 2600-anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Letícia Scussel
LS
Bergamin
Faculdades de Farmácia, Programa de Pós-Graduação em Biologia Celular e Molecular e Instituto de Toxicologia e Farmacologia, Pontificia Universidade Católica do Rio Grande do Sul - PUCRS, Porto Alegre, RS, Brazil.
Fernanda Bueno
FB
Morrone
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, RJ, Brazil.
Robson
R
Coutinho-Silva
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul - UFRGS, 2600-anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Angela Terezinha
AT
de Souza Wyse
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul - UFRGS, 2600-anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Ana Maria Oliveira
AM
Battastini
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D006710:Homocysteine / Q000633:toxicity*; D020138:Hyperhomocysteinemia / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics
D000975:Antioxidants; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D058486:Receptors, Purinergic P2X7; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006710:Homocysteine; D000111:Acetylcysteine
Homocysteine; IL-1β; Macrophages; P2X7 receptor