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RISS 인기검색어
- 검색키워드
- 저자 : Nold-Petry, Claudia A. (검색결과 3 건)
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IL-32-dependent effects of IL-1 on endothelial cell functions
Nold-Petry, C. A.,Nold, M. F.,Zepp, J. A.,Kim, S.-H.,Voelkel, N. F.,Dinarello, C. A. Proceedings of the National Academy of Sciences 2009 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.106 No.10
<P>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.</P>
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Nold-Petry, Claudia A.,Nold, Marcel F.,Nielsen, Jason W.,Bustamante, Alex,Zepp, Jarod A.,Storm, Kathleen A.,Hong, Jae-Woo,Kim, Soo-Hyun,Dinarello, Charles A. American Society for Biochemistry and Molecular Bi 2009 The Journal of biological chemistry Vol.284 No.38
<P>Since interleukin (IL)-18 is a proinflammatory cytokine, mice lacking IL-18 or its ligand-binding receptor (IL-18R) should exhibit decreased cytokine and chemokine production. Indeed, production of IL-1alpha, IL-6, and MIP-1alpha was reduced in IL-18 knock-out (ko) mouse embryonic fibroblast (MEF)-like cells. Unexpectedly, we observed a paradoxical 10-fold increase in IL-1beta-induced IL-6 production in MEF cells from mice deficient in the IL-18R alpha-chain (IL-18Ralpha) compared with wild type MEF. Similar increases were observed for IL-1alpha, MIP-1alpha, and prostaglandin E2. Likewise, coincubation with a specific IL-18Ralpha-blocking antibody augmented IL-1beta-induced cytokines in wild type and IL-18 ko MEF. Stable lines of IL-18Ralpha-depleted human A549 cells were generated using shRNA, resulting in an increase of IL-1beta-induced IL-1alpha, IL-6, and IL-8 compared to scrambled small hairpin RNA. In addition, we silenced IL-18Ralpha with small interfering RNA in primary human blood cells and observed up to 4-fold increases in the secretion of lipopolysaccharide- and IL-12/IL-18-induced IL-1beta, IL-6, interferon-gamma, and CD40L. Mechanistically, despite increases in Stat1 and IL-6, induction of SOCS1 and -3 (suppressor of cytokine signaling 1 and 3) was markedly reduced in the absence of IL-18Ralpha. Consistent with these observations, activation of the p38alpha/beta and ERK1/2 MAPKs and of protein kinase B/Akt increased in IL-18Ralpha ko MEF, whereas the negative feedback kinase MSK2 was more active in IL-18 ko cells. These data reveal a role for SOCS1 and -3 in the seemingly paradoxical hyperresponsive state in cells deficient in IL-18Ralpha, supporting the concept that IL-18Ralpha participates in both pro- and anti-inflammatory responses and that an endogenous ligand engages IL-18Ralpha to deliver an inhibitory signal.</P>
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Endogenous IL-32 controls cytokine and HIV-1 production.
Nold, Marcel F,Nold-Petry, Claudia A,Pott, Gregory B,Zepp, Jarod A,Saavedra, Milene T,Kim, Soo-Hyun,Dinarello, Charles A Williams Wilkins 2008 JOURNAL OF IMMUNOLOGY Vol.181 No.1
<P>IL-32, a proinflammatory cytokine that activates the p38MAPK and NF-kappaB pathways, induces other cytokines, for example, IL-1beta, IL-6, and TNF-alpha. This study investigated the role of endogenous IL-32 in HIV-1 infection by reducing IL-32 with small interfering (si)RNA in freshly infected PBMC and in the latently infected U1 macrophage cell line. When PBMC were pretreated with siRNA to IL-32 (siIL-32), IL-6, IFN-gamma, and TNF-alpha were reduced by 57, 51, and 36%, respectively, compared with scrambled siRNA. Cotransfection of NF-kappaB and AP-1 reporter constructs with siIL-32 decreased DNA binding of these transcription factors by 42 and 46%, respectively. Cytokine protein array analysis revealed that the inhibitory activity of siIL-32 primarily targeted Th1 and proinflammatory cytokines and chemokines, e.g., MIP-1alpha/beta. Unexpectedly, HIV-1 production (as measured by p24) increased 4-fold in these same PBMC when endogenous IL-32 was reduced. Because IFN-gamma was lower in siIL-32-treated PBMC, we blocked IFN-gamma bioactivity, which enhanced the augmentation of p24 by siIL-32. Furthermore, siIL-32 reduced the natural ligands of the HIV-1 coreceptors CCR5 (MIP-1alpha/beta and RANTES) and CXCR4 (SDF-1). Inhibition of endogenous IL-32 in U1 macrophages also increased HIV-1. When rhIL-32gamma was added to these cells, p24 levels fell by 72%; however, in the same cultures IFN-alpha increased 4-fold. Blockade of IFN-alpha/beta bioactivity in IL-32gamma-stimulated U1 cells revealed that IFN-alpha conveys the anti-HIV-1 effect of rhIL-32gamma. In summary, depletion of endogenous IL-32 reduced the levels of Th1 and proinflammatory cytokines but paradoxically increased p24, proposing IL-32 as a natural inhibitor of HIV-1.</P>
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