Low phagocytic activity of resident peritoneal macrophages in diabetic mice: relevance to the formation of advanced glycation end products.

Liu, B F; Miyata, Satoshi; Kojima, Hiroshi; Uriuhara, Atsuko; Kusunoki, Hitomi; Suzuki, Kotaro; Kasuga, Masato

doi:10.2337/diabetes.48.10.2074

Cited by 86 publications

(53 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The diabetic state is known to alter macrophage function resulting in increased lipoprotein lipase production and TNF-␣ release (40). In addition, hyperglycemia, through the generation of advanced glycation end products, increases macrophage secretion of IL-1 and TNF-␣ while enhancing intercellular adhesion molecule 1 expression and decreasing phagocytic activity (41). Because the IRS-2/PI3-kinase pathway is common to both IL-4 and insulin signaling in macrophages, we wanted to demonstrate that IL-4-dependent IRS-2/PI3-kinase signal transduction was inhibited in diabetic macrophages and that the likely mechanism was a result of mTOR-dependent serine phosphorylation of IRS-2 on Ser/ThrPro motifs.…”

mentioning

confidence: 99%

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Hartman

O’Connor

Godbout

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

We have shown previously that hyperinsulinemia inhibits interferon-␣-dependent activation of phosphatidylinositol 3-kinase (PI3-kinase) through mammalian target of rapamycin (mTOR)-induced serine phosphorylation of insulin receptor substrate (IRS)-1. Here we report that chronic insulin and high glucose synergistically inhibit interleukin (IL)-4-dependent activation of PI3-kinase in macrophages via the mTOR pathway. Resident peritoneal macrophages (PerM⌽s) from diabetic (db/db) mice showed a 44% reduction in IRS-2-associated PI3-kinase activity stimulated by IL-4 compared with PerM⌽s from heterozygote (db/؉) control mice. IRS-2 from db/db mouse PerM⌽s also showed a 78% increase in Ser/Thr-Pro motif phosphorylation without a difference in IRS-2 mass. To investigate the mechanism of this PI3-kinase inhibition, 12-O-tetradecanoylphorbol-13-acetate-matured U937 cells were treated chronically with insulin (1 nM, 18 h) and high glucose (4.5 g/liter, 48 h). In these cells, IL-4-stimulated IRS-2-associated PI3-kinase activity was reduced by 37.5%. Importantly, chronic insulin or high glucose alone did not impact IL-4-activated IRS-2-associated PI3-kinase. Chronic insulin ؉ high glucose did reduce IL-4-dependent IRS-2 tyrosine phosphorylation and p85 association by 54 and 37%, respectively, but did not effect IL-4-activated JAK/STAT signaling. When IRS-2 Ser/Thr-Pro motif phosphorylation was examined, chronic insulin ؉ high glucose resulted in a 92% increase in IRS-2 Ser/Thr-Pro motif phosphorylation without a change in IRS-2 mass. Pretreatment of matured U937 cells with rapamycin blocked chronic insulin ؉ high glucose-dependent IRS-2 Ser/Thr-Pro motif phosphorylation and restored IL-4-dependent IRS-2-associated PI3-kinase activity. Taken together these results indicate that IRS-2-dependent IL-4 signaling in macrophages is impaired in models of type 2 diabetes mellitus through a mechanism that relies on insulin/ glucose-dependent Ser/Thr-Pro motif serine phosphorylation mediated by the mTOR pathway.The first member of the insulin receptor substrate (IRS) 1 family, IRS-1, was initially discovered in Fao hepatoma cells as a tyrosine-phosphorylated substrate of the insulin receptor (1). In addition to insulin signaling, IRS proteins are integrally linked to intracellular signaling pathways initiated by IGF-I and the cytokines IL-2, 3, 4, 7, 9, 10, 13, 15 and IFN-␣ and IFN-␥ (2-10). Importantly, serine phosphorylation of IRS-1 blocks insulin, IGF-I, and cytokine signaling through IRS-1 (11-15) and appears critical to the initiation of proteasomedependent IRS-1 degradation (16,17). We have shown that chronic insulin in the presence of high glucose leads to serine phosphorylation of IRS-1 through an mTOR-dependent mechanism and that this renders IRS-1 a poorer substrate for JAK1 (18). In addition, we have shown that serine phosphorylation targets IRS-1 for proteasome-dependent degradation in L6 muscle cells (19). However, these same mechanisms have not been investigated in relation to IRS-2-dependent cytokine signaling.IRS-2 is...

show abstract

mentioning

confidence: 99%

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Hartman

O’Connor

Godbout

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…AGE products produced in diabetic condition were also found to be detrimental to phagocytic activity of peritoneal macrophages [21]. The difference between diabetic and non-diabetic persons was not significant but diabetes was less prevalent in the peritonitis-free group.…”

Section: Peritonitis In Peritoneal Dialysismentioning

confidence: 82%

Microbiology Risk Factors and Outcomes of Peritonitis in Tunisian Peritoneal Dialysis Patients

Lasfar

Guedri

Azzebi

et al. 2018

World J Nephrol Urol

View full text Add to dashboard Cite

show abstract

“…Thus, AGEs themselves have been shown to elicit opposite effects from those have shown here, especially the increase of TNF-α release and suppression of phagocytic ability (18,19), indicating that AGEs may not be the crucial chemical component in the thioglycolate containing Brewer's medium. Macrophages play a key role in the innate response and in the orchestration of an adaptive immune response, by releasing proinflammatory mediators that recruit other immune cells to the site of infection and by processing and presenting antigen to lymphocytes eventually mediating a specific host response.…”

Section: Discussionmentioning

confidence: 99%

Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response

Miksa

Amin

et al. 1998

Int J Mol Med

View full text Add to dashboard Cite

Abstract. In sepsis, phagocytosis and the killing of bacteria by phagocytes are important. Similarly, the clearance of accumulating apoptotic cells is critical in maintaining normal immunity. Upon maturation, peritoneal macrophages (PM) become a major source of proinflammatory cytokines, while losing their efficacy of phagocytosis. However, the underlying mechanism remains unknown. Here we investigated the differential effects of apoptotic thymocytes (AoTC) on TNF-α release in immature thioglycolate-elicited PM (TGPM) and mature resident PM (RPM) in vitro by culturing them with or without AoTC and/or LPS. MFG-E8 expression was assessed using Western blotting and the ability to engulf AoTC was determined histologically. Cytokine secretion was measured by ELISA. MAP kinase phosphorylation was assessed using Western blotting. Mature RPM express <50% of TGPM MFG-E8 levels and have a 30% lower capacity to clear AoTC. The proinflammatory response (TNF-α release) to LPS is 5 times higher, and the capability to phagocytose is decreased along with further down-regulation of MFG-E8 after LPS-stimulation. RPMs also lack phagocytosis-induced inhibition of TNF-α release after LPS stimulation. LPSinduced phosphorylation of ERK1/2, p38 and JNK is more enhanced in RPM compared to TGPM. MFG-E8-mediated apoptotic cell phagocytosis results in an inhibition of MAPK and NFκB signaling pathways. Differential MAPK activation may play a role in the enhanced LPS responsiveness of RPM and the lack of MFG-E8 impedes post-phagocytic suppression of LPS-response through the inhibition of those signaling pathways. These results provide a potential mechanistic insight into the benefit of promoting apoptotic cell clearance via MFG-E8 under inflammatory conditions.

show abstract

Low phagocytic activity of resident peritoneal macrophages in diabetic mice: relevance to the formation of advanced glycation end products.

Cited by 86 publications

References 31 publications

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Microbiology Risk Factors and Outcomes of Peritonitis in Tunisian Peritoneal Dialysis Patients

Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response

Contact Info

Product

Resources

About