Gene interactions and pathways from curated databases and text-mining
Proc Natl Acad Sci U S A 2009, PMID: 19228941

IL-32-dependent effects of IL-1beta on endothelial cell functions.

Nold-Petry, Claudia A; Nold, Marcel F; Zepp, Jarod A; Kim, Soo-Hyun; Voelkel, Norbert F; Dinarello, Charles A

Increasing evidence demonstrates that interleukin (IL)-32 is a pro-inflammatory cytokine, inducing IL-1alpha, IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and chemokines via nuclear factor (NF)-kappaB, p38 mitogen-activated protein kinase (MAPK), and activating protein (AP)-1 activation. Here we report that IL-32 is expressed and is also functional in human vascular endothelial cells (EC) of various origins. Compared with primary blood monocytes, high levels of IL-32 are constitutively produced in human umbilical vein EC (HUVEC), aortic macrovascular EC, and cardiac as well as pulmonary microvascular EC. At concentrations as low as 0.1 ng/ml, IL-1beta stimulated IL-32 up to 15-fold over constitutive levels, whereas 10 ng/ml of TNFalpha or 100 ng/ml of lipopolysaccharide (LPS) were required to induce similar quantities of IL-32. IL-1beta-induced IL-32 was reduced by inhibition of the IkappaB kinase-beta/NF-kappaB and ERK pathways. In addition to IL-1beta, pro-coagulant concentrations of thrombin or fresh platelets increased IL-32 protein up to 6-fold. IL-1beta and thrombin induced an isoform-switch in steady-state mRNA levels from IL-32alpha/gamma to beta/epsilon. Adult EC responded in a similar fashion. To prove functionality, we silenced endogenous IL-32 with siRNA, decreasing intracellular IL-32 protein levels by 86%. The knockdown of IL-32 resulted in reduction of constitutive as well as IL-1beta-induced intercellular adhesion molecule-1 (ICAM-1) (of 55% and 54%, respectively), IL-1alpha (of 62% and 43%), IL-6 (of 53% and 43%), and IL-8 (of 46% and 42%). In contrast, the anti-inflammatory/anti-coagulant CD141/thrombomodulin increased markedly when IL-32 was silenced. This study introduces IL-32 as a critical regulator of endothelial function, expanding the properties of this cytokine relevant to coagulation, endothelial inflammation, and atherosclerosis.

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Text Mining Data

activating protein (AP)-1 → mitogen activated protein kinase: " Increasing evidence demonstrates that interleukin (IL)-32 is a pro-inflammatory cytokine, inducing IL-1alpha, IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and chemokines via nuclear factor (NF)-kappaB, p38 mitogen activated protein kinase ( MAPK ), and activating protein (AP)-1 activation "

activating protein (AP)-1 → (NF)-kappaB: " Increasing evidence demonstrates that interleukin (IL)-32 is a pro-inflammatory cytokine, inducing IL-1alpha, IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and chemokines via nuclear factor (NF)-kappaB , p38 mitogen activated protein kinase ( MAPK ), and activating protein (AP)-1 activation "

IL-32 → IL-1beta: " At concentrations as low as 0.1 ng/ml, IL-1beta stimulated IL-32 up to 15-fold over constitutive levels, whereas 10 ng/ml of TNFalpha or 100 ng/ml of lipopolysaccharide (LPS) were required to induce similar quantities of IL-32 "

IL-32 → IL-1beta: " At concentrations as low as 0.1 ng/ml, IL-1beta stimulated IL-32 up to 15-fold over constitutive levels, whereas 10 ng/ml of TNFalpha or 100 ng/ml of lipopolysaccharide (LPS) were required to induce similar quantities of IL-32 "

IL-32 → IL-1beta: " IL-1beta induced IL-32 was reduced by inhibition of the IkappaB kinase-beta/NF-kappaB and ERK pathways "

intercellular adhesion molecule-1 → IL-1beta: " The knockdown of IL-32 resulted in reduction of constitutive as well as IL-1beta induced intercellular adhesion molecule-1 ( ICAM-1 ) ( of 55 % and 54 %, respectively ), IL-1alpha ( of 62 % and 43 % ), IL-6 ( of 53 % and 43 % ), and IL-8 ( of 46 % and 42 % ) "

Manually curated Databases

No curated data.