IL-10 stimulatory effects on human NK cells explored by gene profile analysis

Mocellin, Simone; Panelli, Monica C.; Wang, E; Róssi, Carlo; Pilati, Pierluigi; Nitti, Donato; Lise, Mario; Marincola, F.M.

doi:10.1038/sj.gene.6364135

Cited by 98 publications

(68 citation statements)

References 53 publications

(40 reference statements)

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“…It has also been reported that IL-10 can induce NK-cell activation. [40][41][42] We also analyzed the effects of splenic NK cells on diffDCs. These splenic NK cells, once activated by diffDCs, partially through IL-10, acquired the ability to lyse surrounding diffDCs but not maDCs.…”

Section: Discussionmentioning

confidence: 99%

TLR agonists promote ERK-mediated preferential IL-10 production of regulatory dendritic cells (diffDCs), leading to NK-cell activation

Qian

Jiang

et al. 2006

Blood

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Regulatory dendritic cells (DCs) play an important role in maintaining peripheral tolerance or immune homeostasis. Our previous study demonstrated that mature DCs could be driven by splenic stroma to proliferate and differentiate into a novel subset of regulatory DCs (diffDCs) displaying a Th2-biased cytokine profile. However, the underlying mechanisms for the unique cytokine profile of diffDCs and how diffDCs regulate the innate and adaptive immunity in response to toll-like receptor (TLR) agonists remain unclear. Here, we report that unlike immature DCs, diffDCs secrete more interleukin 10 (IL-10) but little IL-12p70 in response to lipopolysaccharide (LPS) or other TLR agonists. Up-regulation of extracellular signal-regulated kinase (ERK1/2) activation was shown to be responsible for IL-10 preferential production, and suppression of p38 activation was for impaired IL-12p70 production in diffDCs. Interestingly, LPS treatment could not reverse the inhibitory effect of diffDCs on the proliferation of antigen-specific CD4 ؉ T cells. However, diffDCs could activate natural killer (NK) cells through diffDC-derived IL-10, and even more markedly after stimulation of TLR agonists. These diffDC-activated NK cells could in turn kill surrounding diffDCs. Our results illuminate signal pathways for the unique cytokine profile of diffDCs, and diffDCs can exert their regulatory function even after inflammatory stimuli, thus reflecting one way for strict regulation of immune response. IntroductionDendritic cells (DCs) are the most potent professional antigenpresenting cells (APCs) that integrate a wide array of incoming signals and convey them to lymphocytes, directing the appropriate immune responses. 1 Induction of immune response or tolerance by DCs may be explained by DCs at different developmental stages with different functions, or existence of different subsets of DCs. Immature DCs (imDCs) have been shown to be able to induce tolerance. 2 However, upon inflammatory stimulation or uptake of pathogenic antigens, imDCs migrate to secondary lymph organs undergoing maturation. Mature DCs (maDCs) have a potent immune-stimulatory function by production of cytokines such as interleukin 12 (IL-12) p70, up-regulation of costimulatory molecules, and potent ability to induce Th1 response and activate an antigen-specific CD8 ϩ T-cell response. 3 Recently, subsets of regulatory DCs were identified and considered to be important in maintaining immune homeostasis. [4][5][6] Regulatory DCs negatively regulate immune response by inducing a generation of regulatory T (Treg) cells or a preferential Th2 response. [7][8][9] During investigation of the fate of maDCs after antigen presentation and T-cell activation, we surprisingly found that splenic stromal cells, mimicking the secondary lymph organ microenviroment where maDCs present antigen to lymphocytes, could drive maDCs to proliferate and differentiate into a novel subtype of regulatory DCs (diffDCs), which inhibit rather than activate antigen-specific T-cell proliferation. 10 Compared...

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Section: Discussionmentioning

confidence: 99%

TLR agonists promote ERK-mediated preferential IL-10 production of regulatory dendritic cells (diffDCs), leading to NK-cell activation

Qian

Jiang

et al. 2006

Blood

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“…In mouse macrophages, an inverse correlation was found between FPR2/ALX expression and thromboxane A 2 signaling (38). In NK cells, IL-10 stimulation led to a moderate induction of FPR2/ALX mRNA (34), and the glucocorticoid analog dexamethasone increased the expression of FPR2/ALX mRNA in a time-and dose-dependent manner in PMNs (39,40). Extensive studies in mouse microglial cells identified TNF-a, CD40L, IFN-g, and several ligands for TLRs as regulators of FPR2/ALX receptor expression and function (41)(42)(43)(44)(45).…”

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confidence: 83%

“…Indeed, FPR2/ALX mRNA is expressed in a limited number of primary cells involved in inflammation, such as monocytes (18,32), neutrophils (33), NK cells (34), and possibly T cells (17,35). However, regulation of FPR2/ALX expression is not well understood, with a limited number of regulators identified.…”

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confidence: 99%

Characterization of the Promoter and the Transcriptional Regulation of theLipoxin A4 Receptor(FPR2/ALX) Gene in Human Monocytes and Macrophages

Waechter

Schmid

Herová

et al. 2012

The Journal of Immunology

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The lipoxin A4 receptor FPR2/ALX plays an important part in host defense and inflammation. The receptor binds structurally diverse agonistic ligands, which mainly regulate chemotaxis and activation of leukocytes. However, little is known about the promoter region of the FPR2/ALX gene and its transcriptional regulation in leukocytes. We identified two TATA-less promoter regions, separated by 224 bp, that drive the expression of FPR2/ALX in macrophages. Both promoter regions increased transcription in a reporter assay, and the basal transcription factors OCT1 and SP1 were shown to bind the first and the second promoter, respectively, and to transactivate transcription. Although monocytes expressed high levels of FPR2/ALX mRNA from the second promoter region, differentiation into macrophages abrogated FPR2/ALX expression. Stimulation of macrophages with a set of cytokines revealed that only IFN-γ and LPS increased FPR2/ALX expression from the first promoter to levels similar to those detected in monocytes. The upregulation by IFN-γ is in part mediated by the interaction of IFN regulatory factor 1 with an IFN-responsive sequence element transcription factor binding site located in the first promoter region of the FPR2/ALX gene. However, this upregulation on the mRNA level did not translate into FPR2/ALX protein expression in macrophages owing to reduced translation of the longer mRNA from the first promoter. In contrast, FPR2/ALX mRNA transcribed from the second promoter was translated into surface expression of FPR2/ALX in monocytes. These data support a model in which FPR2/ALX plays a role in chemotaxis and activation of monocytes; however, they also suggest that its function in resident tissue macrophages is limited.

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“…[52][53][54][55] By contrast, IL-10 has a stimulatory effect on human NK-cell cytotoxic activity. 56 All these factors, in a manner similar to IL-4, may differentially contribute to the regulation of the Th1-polarizing pathways sustained by IL-12-and IL-18-conditioned NK cells.…”

Section: Discussionmentioning

confidence: 99%

Human natural killer cells exposed to IL-2, IL-12, IL-18, or IL-4 differently modulate priming of naive T cells by monocyte-derived dendritic cells

Agaugué

Marcenaro

Ferranti

et al. 2008

Blood

124

112

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IntroductionNatural killer (NK) cells and dendritic cells (DCs) are 2 specialized cell types of the innate immunity that act as liaisons between innate and Ag-specific adaptive immune responses. [1][2][3][4] DCs function as sentinels of the immune system and display the unique capability of inducing primary immune responses by providing all the signals necessary to prime naive T cells. 5 NK cells play an active role in innate responses against viruses, bacteria, and tumors thanks to their potent cytotoxic activity and rapid production of cytokines, particularly interferon (IFN)-␥ and tumor necrosis factor (TNF)-␣. 6,7 Because of its important role in shaping the immune response, the crosstalk between NK cells and DCs has been a field of extensive study in recent years. [8][9][10][11][12][13][14][15] It has been shown that the cytolytic activity of fresh NK cells is strongly up-regulated by the interaction with monocyte-derived DCs (MoDCs) that had been exposed to maturation stimuli such as lipopolysaccharide (LPS), interferon (IFN)-␣, or Mycobacterium tuberculosis. [9][10][11][12] Reciprocally, upon interaction with immature DCs (iDCs) in the presence of maturation stimuli, fresh NK cells can strongly enhance DC maturation and cytokine production. 8,10,11,14 In addition, IL-2-activated NK cells could directly induce DC maturation and enhance their ability to stimulate alloproliferative responses of naive CD4 ϩ T cells. 10 In this case, DC maturation occurs at low NK/DC ratios and is dependent on cell-to-cell interactions mediated via the NKp30 and DNAM-1 NK receptors and the release of TNF-␣ and IFN-␥ by NK cells. 8,[13][14][15][16] Regarding the effect exerted by DCs on NK cells, most NK cells become partially activated upon interaction with pathogen-activated DCs, as revealed by the expression of CD69 and by the increase of their cytotoxic activity against different targets.In general, major histocompatibility complex (MHC) class I-deficient aberrant cells are susceptible to NK cell-mediated lysis, whereas normal cells are protected from NK cells because they express MHC class I molecules. iDCs represent a remarkable exception. In an autologous setting, they are highly susceptible to lysis by activated polyclonal NK-cell populations but become resistant when they undergo maturation. 17 Killing of iDCs is confined to those NK cells that lack killer immunoglobulinlike receptor (KIR) specific for self-human leukocyte antigen (HLA) class I alleles and express the HLA-E-specific CD94/ NKG2A inhibitory receptor. 18 Based on these data, an additional function of NK cells would be to keep in check the quality of DCs undergoing maturation in peripheral tissues and to control the amplitude of DC responses and subsequent T-cell priming. This function is based mostly on the ability of NK cells to selectively kill DCs that do not express sufficient amounts of HLA-E at the cell surface. 18,19 Because iDCs express very low amounts of HLA-E molecules that are acquired progressively during DC maturation, NK cells would operate...

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IL-10 stimulatory effects on human NK cells explored by gene profile analysis

Cited by 98 publications

References 53 publications

TLR agonists promote ERK-mediated preferential IL-10 production of regulatory dendritic cells (diffDCs), leading to NK-cell activation

TLR agonists promote ERK-mediated preferential IL-10 production of regulatory dendritic cells (diffDCs), leading to NK-cell activation

Characterization of the Promoter and the Transcriptional Regulation of theLipoxin A4 Receptor(FPR2/ALX) Gene in Human Monocytes and Macrophages

Human natural killer cells exposed to IL-2, IL-12, IL-18, or IL-4 differently modulate priming of naive T cells by monocyte-derived dendritic cells

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