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Insulin influences LPS-induced TNF-± and IL-6 release through distinct pathways in mouse macrophages from different compartments


Diabetic subjects are more susceptible to infections, which is at least partially due to insulin deficiency and hyperglycemia. We hypothesized that insulin influences cytokine release by macrophages stimulated with lipopolysaccharides (LPS) in diabetic C57BL/6 mice. Using bone marrow-derived macrophages (BMDM) from diabetic mice, we showed that LPS induced an increase in TNF-± and IL-6 release and p-p38, p-SAPK/JNK, p-ERK 1/2, and p-Akt (308-Thr and 473-Ser) levels but not p-PKC±/² II and delta. Insulin increased TNF-± and IL-6 secretion in LPS-induced 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-± release, and inhibition with LY294002 decreased both TNF-± and IL-6 after LPS-insulin treatment. PD98059, which inhibits the ERK upstream activators MAPK kinase (MKK) 1 and MKK2, reduced the insulin effect on LPS-induced cytokine release in BMDM. In addition, insulin reduced LPS-induced TNF-±, IL-6 and IL-1² secretion in alveolar and peritoneal macrophages. Accordingly, insulin positively regulated TNF-± and IL-6 secretion by up-regulating p-p38, p-SAPK/JNK, p-ERK 1/2, p-PI3K (p55) and p-Akt (473-Ser). These results suggest that the protective effects of insulin against sepsis likely arise through the modulation of PI3-kinase and ERK 1/2 pathways elicited by LPS in BMDM. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
TESSARO, FERNANDO H. G.; AYALA, THAIS S.; NOLASCO, EDUARDO L.; BELLA, LEONARDO M.; MARTINS, JOILSON O. Insulin Influences LPS-Induced TNF-alpha and IL-6 Release Through Distinct Pathways in Mouse Macrophages from Different Compartments. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, v. 42, n. 5, p. 2093-2104, 2017. Web of Science Citations: 5.

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