Interleukin-6 Induction of Protein S Is Regulated Through Signal Transducer and Activator of Transcription 3

Wolf, Cornelia; Cupers, R; Bertina, Rogier M.; Vos, Hans L.

doi:10.1161/01.atv.0000236202.39165.eb

Cited by 10 publications

(10 citation statements)

References 59 publications

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“…≥20%) in pregnancy in both study groups, although the mean level was significantly higher in the pre-eclampsia group than in the control group. The higher mean levels among cases might arise because protein S is regarded as an active-phase reactant whose levels could be raised in inflammatory states, 19 as seen in pre-eclampsia. This slight increase in protein S levels could also explain the slight increase in mean levels of protein C activity in cases, as observed in the present study, because protein S acts as a cofactor.…”

Section: Discussionmentioning

confidence: 99%

Associations between pre‐eclampsia and protein C and protein S levels among pregnant Nigerian women

Okoye

Eweputanna

Okpani

et al. 2017

Intl J Gynecology & Obste

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Section: Discussionmentioning

confidence: 99%

Associations between pre‐eclampsia and protein C and protein S levels among pregnant Nigerian women

Okoye

Eweputanna

Okpani

et al. 2017

Intl J Gynecology & Obste

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“…In summary, severe hypoxia is now considered associated with gravely ill COVID-19 patients, and IL6 is upregulated in COVID-19 and promotes cis and trans signaling to produce a cytokine storm [ 32 ]. Further, it is reasonable to conclude that subtle clotting begins early in the lungs, perhaps due to an inflammatory reaction in their fine web of blood vessels, which then sets off a cascade of proteins that prompt blood to clot and prevent proper oxygenation.…”

Section: Introductionmentioning

confidence: 99%

“…An overlooked aspect of hypoxia and the IL6-induced cytokine storm is that both factors downregulate a key anticoagulant, Protein S [ 9 , 32 ] ( Figure 1 ). For example, in a population of stroke patients, IL6 was upregulated, and it caused downregulation of Protein S that resulted in venous thrombosis [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

COVID-19: a probable role of the anticoagulant Protein S in managing COVID-19-associated coagulopathy

Chatterjee

Sengupta²,

Majumder

et al. 2020

Aging

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The COVID-19 pandemic has caused monumental mortality, and there are still no adequate therapies. Most severely ill COVID-19 patients manifest a hyperactivated immune response, instigated by interleukin 6 (IL6) that triggers a so called “cytokine storm” and coagulopathy. Hypoxia is also associated with COVID-19. So far overlooked is the fact that both IL6 and hypoxia depress the abundance of a key anticoagulant, Protein S. We speculate that the IL6-driven cytokine explosion plus hypoxemia causes a severe drop in Protein S level that exacerbates the thrombotic risk in COVID-19 patients. Here we highlight a mechanism by which the IL6-hypoxia curse causes a deadly hypercoagulable state in COVID-19 patients, and we suggest a path to therapy.

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“…PS has no enzymatic activity but acts mainly as a cofactor for activated protein C (APC). 1 It participates in the inactivation of factors Va (FVa) and FVIIIa, leading to inhibition of thrombin generation. [2][3][4] Even in absence of APC, PS could still inhibit thrombin generation by decreasing the conversion of prothrombin to thrombin and that of FX to FXa.…”

Section: Introductionmentioning

confidence: 99%

C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S–independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies

Buil

Trégouët

Souto

et al. 2010

Blood

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Through its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, ␣ 7 ␤ 1 , ␣ 6 ␤ 1 , and ␣ 7 ␤ 0 , we conducted a genomewide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locus were found genomewide significantly associated with ␣ 7 ␤ 0 levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPB mRNA expression. The allele associated with increased ␣ 7 ␤ 0 plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [ IntroductionProtein S (PS), a vitamin K-dependent plasma protein, is a key regulator of the coagulation/fibrinolysis cascade. PS has no enzymatic activity but acts mainly as a cofactor for activated protein C (APC). 1 It participates in the inactivation of factors Va (FVa) and FVIIIa, leading to inhibition of thrombin generation. [2][3][4] Even in absence of APC, PS could still inhibit thrombin generation by decreasing the conversion of prothrombin to thrombin and that of FX to FXa. 5 PS is also a cofactor for tissue factor pathway inhibitor (TFPI) for inhibiting FXa. 6 In plasma, PS circulates either in a free form (fPS; ϳ 40%) or as a complex with the C4b-binding protein (C4BP; ϳ 60%). [7][8][9][10] It was initially thought that the C4BP-bound PS was not active and that only the circulating fPS was. [7][8][9] However, more recent works shed new light on a more complex mechanism, as C4BP-PS complex was shown to directly participate in the FVa and FVIIIa inactivation, 11 and C4BP could inhibit APC-catalyzed FVa inactivation even in the absence of PS. 12 Such complex and elusive mechanisms could explain why, despite the key role of PS in the regulation of thrombin generation, its involvement in the susceptibility of venous thrombosis (VT) remains obscure. Although PS deficiency is considered a risk factor for VT, 13-15 total PS and fPS show very little correlation with VT. 16,17 C4BP is a large plasma protein existing in 3 different isoforms, ␣ 7 ␤ 1 , ␣ 7 ␤ 0 , and ␣ 6 ␤ 1 , according to the number of identical ␣-chains (6 or 7) and the presence/absence of a single ␤-chain. 18 The main isoform is ␣ 7 ␤ 1 , whereas the ␣ 7 ␤ 0 isoform lacking the ␤-chain represents approximately 17% of the C4BP molecules. 7,18 Whereas the ␣-chain binds for many ligands, 19 the ␤-chain is specific for the binding of PS. As a consequence, the amount of ␤-chaincontaining isoforms can be viewed as a surrogate marker for fPS levels. Plasma levels of all 3 isoforms have documented high heritability estimates (ϳ 40% each), 20 but little is know ab...

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Interleukin-6 Induction of Protein S Is Regulated Through Signal Transducer and Activator of Transcription 3

Cited by 10 publications

References 59 publications

Associations between pre‐eclampsia and protein C and protein S levels among pregnant Nigerian women

Associations between pre‐eclampsia and protein C and protein S levels among pregnant Nigerian women

COVID-19: a probable role of the anticoagulant Protein S in managing COVID-19-associated coagulopathy

C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S–independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies

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