Interleukin-10 Induction of Nitric-oxide Synthase Expression Attenuates CD40-mediated Interleukin-12 Synthesis in Human Endothelial Cells

Cattaruzza, Marco; Slodowski, Wojchiech; Stojakovic, Milica; Krzesz, Robert; Hecker, Markus

doi:10.1074/jbc.m301670200

Cited by 50 publications

(49 citation statements)

References 29 publications

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“…could become more responsive to IL-10 during an inflammatory episode (4). De novo synthesis of the receptor could be one explanation for the rapid upregulation of hIL-10 expression after cmvIL-10 treatment.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Interleukin-10 Downregulates Metalloproteinase Activity and Impairs Endothelial Cell Migration and Placental Cytotrophoblast Invasiveness In Vitro

Yamamoto-Tabata¹,

McDonagh²,

Chang³

et al. 2004

J Virol

125

105

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At the uterine-placental interface, fetal cytotrophoblasts invade the decidua, breach maternal blood vessels, and form heterotypic contacts with uterine microvascular endothelial cells. In early gestation, differentiatinginvading cytotrophoblasts produce high levels of matrix metalloproteinase 9 (MMP-9), which degrades the extracellular matrix and increases the invasion depth. By midgestation, when invasion is complete, MMP levels are reduced. Cytotrophoblasts also produce human interleukin-10 (hIL-10), a pleiotropic cytokine that modulates immune responses, helping to protect the fetal hemiallograft from rejection. Human cytomegalovirus (CMV) is often detected at the uterine-placental interface. CMV infection impairs cytotrophoblast differentiation and invasion, altering the expression of the cell adhesion and immune molecules. Here we report that infection with a clinical CMV strain, VR1814, but not a laboratory strain, AD169, downregulates MMP activity in uterine microvascular endothelial cells and differentiating-invading cytotrophoblasts. Infected cytotrophoblasts expressed CMV IL-10 (cmvIL-10) mRNA and secreted the viral cytokine, which upregulated hIL-10. Functional analyses showed that cmvIL-10 treatment impaired migration in endothelial cell wounding assays and cytotrophoblast invasion of Matrigel in vitro. Comparable changes occurred in cells that were exposed to recombinant hIL-10 or cmvIL-10. Our results show that cmvIL-10 decreases MMP activity and dysregulates the cell-cell and/or cell-matrix interactions of infected cytotrophoblasts and endothelial cells. Reduced MMP activity early in placental development could impair cytotrophoblast remodeling of the uterine vasculature and eventually restrict fetal growth in affected pregnancies.

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Interleukin-10 Downregulates Metalloproteinase Activity and Impairs Endothelial Cell Migration and Placental Cytotrophoblast Invasiveness In Vitro

Yamamoto-Tabata¹,

McDonagh²,

Chang³

et al. 2004

J Virol

125

105

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“…However, an altered function of neutrophilic granulocytes, dendritic cells, or mast cells may also contribute to the acceleration of tissue repair in the mutant animals. In addition, we cannot exclude direct effects of IL-10 on proliferation, migration, and function of resident cells including fibroblasts, 32,33 endothelial cells, 34 or keratinocytes. 35 Based on distinct cytokine profiles and biological functions subsets of activated macrophages have been identified.…”

Section: Discussionmentioning

confidence: 99%

Accelerated Wound Closure in Mice Deficient for Interleukin-10

Eming

Werner

Bugnon

et al. 2007

The American Journal of Pathology

160

133

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The impact of the local inflammatory response on the process of wound healing has been debated for decades. In particular, the question whether infiltrating macrophages and granulocytes promote or impede tissue repair has received much attention. In the present study, we show that wound healing is accelerated in mice deficient for the anti-inflammatory cytokine interleukin (IL)-10. IL-10 ؊/؊ mice closed excisional wounds significantly earlier compared with IL-10-competent control littermates. This effect was attributable to accelerated epithelialization as well as enhanced contraction of the wound tissue in the mutant animals. Increased ␣-smooth muscle actin expression in IL-10-deficient mice suggests that augmented myofibroblast differentiation is responsible for the enhanced contraction of wounds in mutant mice. The number of macrophages infiltrating the wound tissue was significantly increased in IL-10 ؊/؊ mice compared with control littermates suggesting that this cell type mediates the accelerated tissue repair. These results show for the first time that IL-10 can impede wound repair.

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“…In addition, IL-10 inhibits the expression of adhesion molecules and matrix metalloproteinases, as well as smooth muscle cell proliferation. [24][25][26][27][28] These IL-10 effects might regulate local vascular inflammation and remodeling, also leading to an improvement in arteriolosclerosis. Clearly, further investigations are required to clarify the mechanism(s) by which IL-10 improves hypertension-associated vascular damage in more detail.…”

Section: Discussionmentioning

confidence: 99%

Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat

et al. 2008

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Interleukin-10 (IL-10) ameliorates various T-helper type 1 cellmediated chronic inflammatory diseases. Although the therapeutic benefits of IL-10 include antiatherosclerotic effects, pathophysiological effects of IL-10 on vascular remodeling in hypertension have not yet been elucidated. These studies were designed to determine whether sustained IL-10 expression, mediated by an adeno-associated virus (AAV) vector, prevents vascular remodeling and target-organ damage in the stroke-prone spontaneously hypertensive rat (SHR-SP)-an animal model of malignant hypertension. A single intramuscular injection of an AAV1 vector encoding rat IL-10 introduced long-term IL-10 expression. These IL-10-transduced rats had decreased stroke episodes and proteinuria, resulting in improved survival. Histological examination revealed a reduced level of deleterious vascular remodeling of resistance vessels in the brain and kidney of these rats. Immunohistochemical analysis indicated that IL-10 inhibited the enhanced renal transforming growth factor-b expression and perivascular infiltration of monocytes/macrophages and nuclear factor-kB-positive cells normally observed in the SHR-SP. Four weeks after IL-10 vector injection, systolic blood pressure significantly decreased and this effect persisted for several months. Overall, AAV vector-mediated systemic IL-10 expression prevented vascular remodeling and inflammatory lesions of target organs in the SHR-SP. This approach provides significant insights into the prevention strategy of disease onset with unknown genetic predisposition or intractable polygenic disorders.

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Interleukin-10 Induction of Nitric-oxide Synthase Expression Attenuates CD40-mediated Interleukin-12 Synthesis in Human Endothelial Cells

Cited by 50 publications

References 29 publications

Human Cytomegalovirus Interleukin-10 Downregulates Metalloproteinase Activity and Impairs Endothelial Cell Migration and Placental Cytotrophoblast Invasiveness In Vitro

Human Cytomegalovirus Interleukin-10 Downregulates Metalloproteinase Activity and Impairs Endothelial Cell Migration and Placental Cytotrophoblast Invasiveness In Vitro

Accelerated Wound Closure in Mice Deficient for Interleukin-10

Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat

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