Insulin inhibits tissue factor expression in monocytes

Abstract

Summary. Objectives: Platelets from healthy subjects are inhibited by insulin but type 2 diabetes mellitus (T2DM) platelets have become insulin-resistant, which might explain their hyperactivity. In the present study we investigated whether monocytes are responsive to insulin. Methods and results: LPSinduced tissue factor (TF) upregulation was measured in human monocytes and monocytic THP-1 cells in a factor Xa generation assay.) induced a dose-dependent inhibition in both cell types and in monocytes 100 nmol L )1 insulin inhibited cytosolic, membrane-bound and microparticle TF by 32 ± 2, 27 ± 3 and 52 ± 4% (n = 3). Insulin induced Tyr phosphorylation of the insulin receptor (INS-R) and formation of an INS-R -G i a 2 complex, suggesting interference with LPS-induced cAMP control. Indeed, insulin interfered with LPS-induced cAMP decrease and TF upregulation in a manner similar to an inhibitor of G i (pertussis toxin) and agents that raise cAMP (iloprost, forskolin, IBMX) reduced TF upregulation. Although LPS failed to raise cytosolic Ca 2+ , quenching of Ca 2+ increases (BAPTA-AM) reduced and induction of Ca 2+ entry (ionophore, P2X7 activation) enhanced upregulation of TF mRNA and procoagulant activity. Insulin interfered with MCP-1-induced Ca 2+ mobilization but not with ATP-induced Ca 2+ rises. Conclusions: Insulin inhibits TF expression in monocytes and monocyte-derived microparticles through interference with G i a 2 -mediated cAMP suppression, which attenuates Ca 2+ -mediated TF synthesis.

Resolvin D1 Stimulates Alveolar Fluid Clearance through Alveolar Epithelial Sodium Channel, Na,K-ATPase via ALX/cAMP/PI3K Pathway in Lipopolysaccharide-Induced Acute Lung Injury

“…A previous study showed that LPS-induced immune response leads to a decrease of intracellular cAMP (55). Another study showed that LPS activates G i , thereby inhibiting AC and formation of cAMP (56). Stimulation with cAMP not only increases Na + transport within 5 min, but also promotes Na,K-ATPase recruitment to the plasma membrane (57,58).…”

Induction of insulin resistance by the adipokines resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 in human megakaryocytes

“…In healthy individuals, insulin interferes with the suppression of cAMP and accumulation of this inhibitor attenuates platelet functions and monocyte responses. 9,10 The insulin resistance observed in type 2 diabetes rescues the fall in cAMP, which promotes aggregation, secretion and procoagulant activity in platelets and tissue factor synthesis and interleukin-1β secretion in monocytes. Insulin also inhibits splicing of tissue factor pre-mRNA in platelets adhering to prothrombotic proteins and the loss of insulin responsiveness in type 2 diabetes might well contribute to the thrombogenicity of the platelet plug that forms upon plaque rupture.…”

Modulation of epithelial sodium channel in human alveolar epithelial cells by lipoxin A4 through AhR-cAMP-dependent pathway

“…Studies have shown that AhR induces signaling pathways that entail ERK, PKA, MMP9 and cAMP, cGMP and Ca 2+ [22]. It has also been shown that AhR is more sensitive to the cAMP signaling pathway [22,23], and that cAMP induces nuclear translocation of the AhR [24]. Thus it appears that the two signaling pathways for regulation of ENaC, cAMP, and cGMP are compartmentalized.…”

“…Extracellular signals also interact with GPCR to activate guanylyl cyclases (GC) and increase intracellular cGMP levels. Studies have shown that AhR induces signaling pathways that entail ERK, PKA, MMP9 and cAMP, cGMP and Ca 2+ [22]. It has also been shown that AhR is more sensitive to the cAMP signaling pathway [22,23], and that cAMP induces nuclear translocation of the AhR [24].…”