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PubMed: 24464629

Title
Heme induces IL-1β secretion through activating NLRP3 in kidney inflammation.
Journal
Cell biochemistry and biophysics
Volume
69
Issue
None
Pages
495-502
Date
2014-07-01
Authors
Fu W | Ji Z | Li Q | Li W | Wang Y | Yan J | Yao J | Zhou Z

Evidence 0b323d75ba
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As a component of hemoglobin, free heme is released when hemolysis or extensive cell damage occur which results in inflammatory response.

a(CHEBI:heme) positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

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bp(GO:"inflammatory response") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence acbd5d63e9
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Free heme is generated by intra- and extra-vascular hemolysis or extensive cell damage [14, 15].

a(CHEBI:heme) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

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path(MESH:Hemolysis) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence ba78abcc07
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Free heme is a dangerous molecule which can be recognized and degenerated by stress-responsive enzyme oxygenase- 1 (HO-1) [16] which plays an essential role in host defense against heme.

deg(a(CHEBI:heme)) positiveCorrelation p(HGNC:HMOX1) View Subject | View Object

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p(HGNC:HMOX1) positiveCorrelation deg(a(CHEBI:heme)) View Subject | View Object

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Evidence bff9c2961d
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Free heme has been proved possess pro-inflammatory activities, such as leukocyte activation, migration and infiltration, adhesion molecules activation, and cytokines and acute phase proteins induction [17, 18].

a(CHEBI:heme) positiveCorrelation bp(GO:"leukocyte activation") View Subject | View Object

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a(CHEBI:heme) positiveCorrelation a(MESH:"Cell Adhesion Molecules") View Subject | View Object

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a(CHEBI:heme) positiveCorrelation a(MESH:Cytokines) View Subject | View Object

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a(MESH:"Cell Adhesion Molecules") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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a(MESH:Cytokines) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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bp(GO:"leukocyte activation") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence 2d0d0d2009
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ELISA analysis displayed that the concentration of IL-1b in culture supernatants was significantly enhanced after stimulated by heme and PPIX.

a(CHEBI:heme) increases p(MGI:Il1b) View Subject | View Object

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a(CHEBI:protoporphyrin) increases p(MGI:Il1b) View Subject | View Object

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Evidence b5895c0f20
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The effect of heme on IL-1b production initiated as early as 4 h after stimulation and displayed strict time- and dose-dependent manner (Fig. 1a– d).

a(CHEBI:heme) increases p(MGI:Il1b) View Subject | View Object

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Evidence cf2b99f9e4
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These results demonstrate that heme could efficiently induce maturation and secretion of IL-1b in macrophages and primarily suggested that heme participates in immune response.

a(CHEBI:heme) increases p(MGI:Il1b) View Subject | View Object

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Cell Ontology (CL)
macrophage
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Kidney
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Evidence a26e2dec63
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Western blotting results showed that the p10 active form of caspase-1 was detected in macrophages incubated with heme for 12 h.

a(CHEBI:heme) positiveCorrelation act(p(MGI:Casp1)) View Subject | View Object

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macrophage
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act(p(MGI:Casp1)) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence 08602fe183
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These results suggest that heme induces maturation and secretion of IL-1b in macrophages through activating caspase-1 (Fig. 2a).

a(CHEBI:heme) positiveCorrelation act(p(MGI:Casp1)) View Subject | View Object

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macrophage
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act(p(MGI:Casp1)) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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act(p(MGI:Casp1)) increases p(MGI:Il1b) View Subject | View Object

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Evidence 018d3bf4ff
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These results demonstrate that free heme induces IL-1b through activating NLRP3 inflammasome via ASC and suggest that free heme plays an essential role in inflammation response as a dangerous signal.

a(CHEBI:heme) positiveCorrelation act(p(MGI:Nlrp3)) View Subject | View Object

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p(MGI:Il1b) positiveCorrelation act(p(MGI:Nlrp3)) View Subject | View Object

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act(p(MGI:Nlrp3)) positiveCorrelation p(MGI:Il1b) View Subject | View Object

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macrophage
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act(p(MGI:Nlrp3)) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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macrophage
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Evidence d1576544dd
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These results strongly suggest that heme activates NLRP3 through P2X receptors, especially P2X4R and P2X7R.

a(CHEBI:heme) positiveCorrelation p(MGI:P2rx7) View Subject | View Object

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a(CHEBI:heme) positiveCorrelation p(MGI:P2rx4) View Subject | View Object

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act(p(MGI:Nlrp3)) positiveCorrelation p(MGI:P2rx7) View Subject | View Object

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macrophage
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act(p(MGI:Nlrp3)) positiveCorrelation p(MGI:P2rx4) View Subject | View Object

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macrophage
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Kidney
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p(MGI:P2rx4) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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macrophage
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p(MGI:P2rx4) positiveCorrelation act(p(MGI:Nlrp3)) View Subject | View Object

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macrophage
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p(MGI:P2rx7) positiveCorrelation act(p(MGI:Nlrp3)) View Subject | View Object

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macrophage
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p(MGI:P2rx7) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence eef040701e
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The results showed that enforced HO-1 could efficiently decline the heme level in the lysates of ligated kidneys, and inhibit kidney inflammation characterized by down-regulation of NLRP3-Caspase- 1-IL-1b axis.

a(CHEBI:heme) negativeCorrelation p(MGI:Hmox1) View Subject | View Object

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p(MGI:Casp1) negativeCorrelation p(MGI:Hmox1) View Subject | View Object

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p(MGI:Hmox1) negativeCorrelation a(CHEBI:heme) View Subject | View Object

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p(MGI:Hmox1) decreases path(MESH:Inflammation) View Subject | View Object

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p(MGI:Hmox1) negativeCorrelation p(MGI:Nlrp3) View Subject | View Object

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p(MGI:Hmox1) negativeCorrelation p(MGI:Casp1) View Subject | View Object

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p(MGI:Hmox1) negativeCorrelation p(MGI:Il1b) View Subject | View Object

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p(MGI:Il1b) negativeCorrelation p(MGI:Hmox1) View Subject | View Object

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p(MGI:Nlrp3) negativeCorrelation p(MGI:Hmox1) View Subject | View Object

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Evidence 83dd27c2c2
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These results suggest that heme plays an essential role in kidney inflammation via regulating NLRP3-Caspase-1-IL-1b axis.

a(CHEBI:heme) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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macrophage
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Kidney
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path(MESH:Inflammation) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence 13ce6adf0a
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IL-1b participates in a robust inflammatory response.

bp(GO:"inflammatory response") positiveCorrelation p(HGNC:IL1B) View Subject | View Object

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p(HGNC:IL1B) positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

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Evidence c2aa05c63c
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As a component of inflammasome, NLRP3 is the best characterized member of NLRs, which recruits and activates caspase-1 via the adapter molecule ASC (apoptosis- associated speck-like protein containing caspase activation and recruitment domain) [8, 9].

p(HGNC:CASP1) positiveCorrelation p(HGNC:NLRP3) View Subject | View Object

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p(HGNC:NLRP3) positiveCorrelation p(HGNC:CASP1) View Subject | View Object

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Evidence a1c99b063a
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These results suggest that heme induced activation of NLRP3-Caspase-1-IL-1b axis is involved in kidney inflammation in mice UUO model and that heme serves as a dangerous factor participates in this process.

p(MGI:Casp1) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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p(MGI:Il1b) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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macrophage
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p(MGI:Nlrp3) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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path(MESH:Inflammation) positiveCorrelation p(MGI:Nlrp3) View Subject | View Object

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path(MESH:Inflammation) positiveCorrelation p(MGI:Casp1) View Subject | View Object

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path(MESH:Inflammation) positiveCorrelation p(MGI:Il1b) View Subject | View Object

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Evidence 04eb313271
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Knockdown of ASC significantly inhibits the secretion of IL-1b, which primarily suggests that Inflammation/ASC axis is involved in the heme-mediated maturation and secretion of IL-1b (Fig. 2b).

p(MGI:Il1b) positiveCorrelation act(p(MGI:Pycard)) View Subject | View Object

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act(p(MGI:Pycard)) positiveCorrelation p(MGI:Il1b) View Subject | View Object

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Evidence fca05d2c7b
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As expected, NLRP3+/+ macrophages were efficiently stimulated to secrete IL-1b by heme, and displayed dose-dependent (up to 40 lM) manner.

p(MGI:Il1b) positiveCorrelation act(p(MGI:Nlrp3)) View Subject | View Object

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act(p(MGI:Nlrp3)) positiveCorrelation p(MGI:Il1b) View Subject | View Object

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Evidence f3762c672c
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Western blotting showed that deficiency of P2X7R partially inhibited the secretion of mature IL-1b that heme induced (Fig. 3c).

p(MGI:Il1b) positiveCorrelation p(MGI:P2rx7) View Subject | View Object

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p(MGI:P2rx7) positiveCorrelation p(MGI:Il1b) View Subject | View Object

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Evidence ae566ee0b1
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Therefore, knockdown of P2X4R and double knockdown of P2X7R plus P2X4R were performed by shRNA in macrophages and the result showed that P2X4R knockdown also partially inhibit the heme induced IL-1b secretion and double knockdown of P2X7R plus P2X4R almost completely depressed the IL-1b secretion (Fig. 3d).

p(MGI:Il1b) positiveCorrelation p(MGI:P2rx4) View Subject | View Object

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p(MGI:P2rx4) positiveCorrelation p(MGI:Il1b) View Subject | View Object

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Evidence c2572ce34a
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Furthermore, P2X7R was reported that participates in NLRP3 activation in renal inflammation and injury induced by high-fat diet [29].

act(p(MGI:Nlrp3)) positiveCorrelation p(MGI:P2rx7) View Subject | View Object

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macrophage
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p(MGI:P2rx7) positiveCorrelation act(p(MGI:Nlrp3)) View Subject | View Object

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macrophage
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Kidney
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Evidence 669b9f04d4
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Kidney inflammation is the major pathologic process of chronic kidney disease (CKD) and acute kidney injury (AKI) which cause significant morbidity and mortality in the general population [1].

path(HP:"Acute kidney injury") positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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path(HP:"Chronic kidney disease") positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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Kidney
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path(MESH:Inflammation) positiveCorrelation path(HP:"Chronic kidney disease") View Subject | View Object

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Kidney
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path(MESH:Inflammation) positiveCorrelation path(HP:"Acute kidney injury") View Subject | View Object

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