Gene interactions and pathways from curated databases and text-mining
Blood 2008, PMID: 18684863

HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB-dependent caspase-1 activation.

Kuijk, Loes M; Beekman, Jeffrey M; Koster, Janet; Waterham, Hans R; Frenkel, Joost; Coffer, Paul J

Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder characterized by recurring fever episodes and results from disturbed isoprenoid biosynthesis. Lipopolysaccharide-stimulated peripheral blood mononuclear cells from MKD patients secrete high levels of interleukin-1beta (IL-1beta) because of the presence of hyperactive caspase-1, and this has been proposed to be the primary cause of recurring inflammation. Here we show that inhibition of HMG-CoA reductase by simvastatin treatment, mimicking MKD, results in increased IL-1beta secretion in a Rac1/PI3K-dependent manner. Simvastatin treatment was found to activate protein kinase B (PKB)/c-akt, a primary effector of PI3K, and ectopic expression of constitutively active PKB was sufficient to induce IL-1beta release. The small GTPase Rac1 was activated by simvastatin, and this was required for both PKB activation and IL-1beta secretion. IL-1beta release is mediated by caspase-1, and simvastatin treatment resulted in increased caspase-1 activity in a Rac1/PI3K-dependent manner. These data suggest that, in MKD, dysregulated isoprenoid biosynthesis activates Rac1/PI3K/PKB, resulting in caspase-1 activation with increased IL-1beta release. Importantly, inhibition of Rac1 in peripheral blood mononuclear cells isolated from MKD patients resulted in a dramatic reduction in IL-1beta release. These data suggest that pharmacologic inhibition of Rac1 could provide a novel therapeutic strategy for treatment of MKD.

Diseases/Pathways annotated by Medline MESH: Mevalonate Kinase Deficiency
Document information provided by NCBI PubMed

Text Mining Data

caspase-1 ⊣ HMG-CoA reductase: " HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB dependent caspase-1 activation "

HMG-CoA reductase ⊣ IL-1beta: " HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB dependent caspase-1 activation "

caspase-1 → Rac1/PI3K/PKB: " HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB dependent caspase-1 activation "

caspase-1 → IL-1beta: " HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB dependent caspase-1 activation "

caspase-1 → Rac1/PI3K/PKB: " HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB dependent caspase-1 activation "

caspase-1 → Rac1/PI3K/PKB: " HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB dependent caspase-1 activation "

IL-1beta ⊣ HMG-CoA reductase: " Here we show that inhibition of HMG-CoA reductase by simvastatin treatment, mimicking MKD, results in increased IL-1beta secretion in a Rac1/PI3K dependent manner "

IL-1beta — Rac1/PI3K: " Here we show that inhibition of HMG-CoA reductase by simvastatin treatment, mimicking MKD, results in increased IL-1beta secretion in a Rac1/PI3K dependent manner "

IL-1beta — Rac1/PI3K: " Here we show that inhibition of HMG-CoA reductase by simvastatin treatment, mimicking MKD, results in increased IL-1beta secretion in a Rac1/PI3K dependent manner "

IL-1beta → PKB: " Simvastatin treatment was found to activate protein kinase B (PKB)/c-akt, a primary effector of PI3K, and ectopic expression of constitutively active PKB was sufficient to induce IL-1beta release "

PKB → Rac1: " The small GTPase Rac1 was activated by simvastatin, and this was required for both PKB activation and IL-1beta secretion "

IL-1beta → Rac1: " The small GTPase Rac1 was activated by simvastatin, and this was required for both PKB activation and IL-1beta secretion "

IL-1beta → caspase-1: " IL-1beta release is mediated by caspase-1 , and simvastatin treatment resulted in increased caspase-1 activity in a Rac1/PI3K dependent manner "

caspase-1 — Rac1/PI3K: " IL-1beta release is mediated by caspase-1, and simvastatin treatment resulted in increased caspase-1 activity in a Rac1/PI3K dependent manner "

caspase-1 — Rac1/PI3K: " IL-1beta release is mediated by caspase-1, and simvastatin treatment resulted in increased caspase-1 activity in a Rac1/PI3K dependent manner "

IL-1beta ⊣ Rac1: " Importantly, inhibition of Rac1 in peripheral blood mononuclear cells isolated from MKD patients resulted in a dramatic reduction in IL-1beta release "

Manually curated Databases

No curated data.