Insulin Influences LPS-Induced TNF-alpha and IL-6 Release Through Distinct Pathways in Mouse Macrophages from Different Compartments

Author(s)

Tessaro, Fernando H. G. ^[1] ; Ayala, Thais S. ^[1] ; Nolasco, Eduardo L. ^[1] ; Bella, Leonardo M. ^[1] ; Martins, Joilson O. ^[1]

Affiliation

^[1] Univ Sao Paulo FCF USP, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Lab Immunoendocrinol, Sao Paulo - Brazil

• Document type: Journal article
• Source: CELLULAR PHYSIOLOGY AND BIOCHEMISTRY; v. 42, n. 5, p. 2093-2104, 2017.
• Web of Science Citations: 5

Abstract

Background/Aims: Diabetic subjects are more susceptible to infections, which is partially due to insulin deficiency and hyperglycemia. We hypothesized that insulin influences cytokine release by macrophages from diabetic C57BL/6 mice stimulated with lipopolysaccharides (LPS). Methods: Bone marrow-derived macrophages (BMDM) and tissue-specific macrophages from diabetic (alloxan 60 mg/kg, i.v.) male C57BL/6 mice were stimulated by LPS (100 ng/mL) and/or treated by insulin (1 mU/mL). Results: Using BMDM from diabetic mice, we showed that LPS induced an increase in TNF-alpha and IL-6 release and p38, SAPK/JNK, ERK 1/2, and Akt (308-Thr and 473-Ser) phosphorylation but not in PKC alpha/beta II and delta. Insulin increased TNF-alpha and IL-6 secretion in LPS-stimulated macrophages as well as p-p38, p-SAPK/JNK, p-ERK 1/2, p-PI3K (p55) and p-Akt (473-Ser) expression. Furthermore, PI3-kinase inhibition by wortmannin decreased TNF-alpha release, and inhibition by LY294002 decreased both TNF-alpha and IL-6 levels after LPS-insulin treatment. PD98059, which inhibits the ERK upstream activators MAPK kinase (MKK) 1 and MKK2, reduced the effect promoted by insulin in BMDM stimulated by LPS In tissue-specific macrophages, insulin reduced LPS-induced TNF-alpha, IL-6 and IL-1 beta secretion in alveolar and peritoneal macrophages. Conclusion: These data suggest that insulin through the modulation of PI3-kinase and ERK 1/2 pathways drive different responses in macrophages, thereby enhancing our understanding of the plasticity of these cells. (C) 2017 The Author(s) Published by S. Karger AG, Basel (AU)

• FAPESP's process: 14/05214-1 - Investigating the role of insulin in different infections in diabetic and healthy animals
• Grantee: Joilson de Oliveira Martins
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/15625-7 - Insulin influences LPS-induced TNF-± and IL-6 release through distinct pathways in mouse macrophages from different compartments
• Grantee: Joilson de Oliveira Martins
• Support Opportunities: Regular Research Grants - Publications - Scientific article
• FAPESP's process: 12/23998-4 - Influence of vitamin D receptor expression (VDR and TLR) in macrophages in the model of experimental diabetes mellitus
• Grantee: Leonardo Mendes Bella
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 10/02272-0 - Effect of insulin on lung inflammation in animal with sepsis, innate immunit,activation of insulin gene (BGK) and insulin receptors (IR)-A and IR-B
• Grantee: Joilson de Oliveira Martins
• Support Opportunities: Research Grants - Young Investigators Grants