| 1. |
- Dietrich, Nicole, et al.
(författare)
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Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria.
- 2010
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:19, s. 8748-8753
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Tidskriftsartikel (refereegranskat)abstract
- Balanced induction of proinflammatory and type I IFN responses upon activation of Toll-like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmunity. However, their role in antimicrobial host defenses is being acknowledged increasingly. How mast cells interact with microbes and the nature of responses triggered thereby is not well characterized. Here we show that in response to TLR activation by Gram-positive and -negative bacteria or their components, mast cells elicit proinflammatory but not type I IFN responses. We demonstrate that in mast cells, bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization, a prerequisite for type I IFN induction. Such cells, however, can elicit type I IFNs in response to vesicular stomatitis virus which accesses the cytosolic retinoic acid-inducible gene I receptor. Although important for antiviral immunity, a strong I IFN response is known to contribute to pathogenesis of several bacterial pathogens such as Listeria monocytogenes. Interestingly, we observed that the mast cell-dependent neutrophil mobilization upon L. monocytogenes infection is highly impaired by IFN-beta. Thus, the fact that mast cells, although endowed with the capacity to elicit type I IFNs in response to viral infection, elicit only proinflammatory responses upon bacterial infection shows that mast cells, key effector cells of the innate immune system, are well adjusted for optimal antibacterial and antiviral responses.
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| 2. |
- Gacic, Jelena, et al.
(författare)
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Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages
- 2016
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Ingår i: Pharmacological Reports. - : POLISH ACAD SCIENCES INST PHARMACOLOGY. - 1734-1140 .- 2299-5684. ; 68:1, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Imatinib mesylate (Glivec, formerly STI-571) is a selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, there are reports suggesting that imatinib could be atheroprotective by lowering plasma low-density lipoprotein (LDL). Aim: To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity. Methods and results: Uptake of fluorescence-labeled LDL was analyzed using flow cytometry. Macrophages treated with imatinib showed a 23.5%, 27%, and 15% decrease in uptake of native LDL (p < 0.05), acetylated LDL (p < 0.01), and copper-modified oxidized LDL (p < 0.01), respectively. Gel based zymography showed that secretion and activity of MMP-2 and MMP-9 were inhibited by imatinib. Using GeneChip Whole Transcript Expression array analysis, no obvious gene candidates involved in the mechanisms of cholesterol metabolism or MMP regulation were found to be affected by imatinib. Instead, we found that imatinib up-regulated microRNA 155 (miR155) by 43.8% and down-regulated ADAM metallopeptidase domain 28 (ADAM28) by 41.4%. Both genes could potentially play an atheroprotective role and would be interesting targets in future studies. Conclusion: Our results indicate that imatinib causes post-translational inhibition with respect to cholesterol uptake and regulation of MMP-2 and MMP-9. More research is needed to further evaluate the role of imatinib in the regulation of other genes and processes. (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
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| 3. |
- Gekara, Nelson O., et al.
(författare)
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Listeria monocytogenes induces T cell receptor unresponsiveness through pore-forming toxin listeriolysin O
- 2010
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 202:11, s. 1698-1707
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Tidskriftsartikel (refereegranskat)abstract
- Background: The success of many pathogens relies on their ability to circumvent the innate and adaptive immune defenses. How bacterial pathogens subvert adaptive immune defenses is not clear. Cholesterol-dependent cytolysins (CDCs) represent an expansive family of homologous pore-forming toxins that are produced by more than 20 gram-positive bacterial species. Listeriolysin O (LLO), a prototype CDC, is the main virulence factor of Listeria monocytogenes.Methods: We employed flow cytometric and microarray techniques to analyze the effect of LLO on T cell activation in vitro and in vivo.Results: In vivo and in vitro proliferation of CD4+T cells upon T cell receptor (TCR) activation was highly diminished in the presence of LLO or wild-type L. monocytogenes but not in the presence of LLO-deficient L. monocytogenes. This block in T cell proliferation was specific to T cell activation via the TCR and not by phorbol 12-myristate 13-acetate-ionomycin, which bypasses the proximal TCR signaling event. The results of microarray analysis suggest that LLO-induced T cell unresponsiveness is due to the induction of a calcium-nuclear factor of activated T cells-dependent transcriptional program that drives the expression of negative regulators of TCR signaling.Conclusion: These findings provide important insights into how bacterial toxins silence adaptive immune responses and thus enable prolonged survival of the pathogen in the host.
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| 4. |
- Gustafsson (Lidström), Charlotte, et al.
(författare)
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Gene expression profiling of human decidual macrophages : Evidence for immunosuppressive phenotype
- 2008
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:4, s. e2078-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although uterine macrophages are thought to play an important regulatory role at the maternal-fetal interface, their global gene expression profile is not known. Methodology/Principal Findings: Using micro-array comprising approximately 14,000 genes, the gene expression pattern of human first trimester decidual CD14+ monocytes/macrophages was characterized and compared with the expression profile of the corresponding cells in blood. Some of the key findings were confirmed by real time PCR or by secreted protein. A unique gene expression pattern intrinsic of first trimester decidual CD14+ cells was demonstrated. A large number of regulated genes were functionally related to immunomodulation and tissue remodelling, corroborating polarization patterns of differentiated macrophages mainly of the alternatively activated M2 phenotype. These include known M2 markers such as CCL-18, CD209, insulin-like growth factor (IGF)-1, mannose receptor c type (MRC)-1 and fibronectin-1. Further, the selective up-regulation of triggering receptor expressed on myeloid cells (TREM)-2, alpha-2-macroglobulin (A2M) and prostaglandin D2 synthase (PGDS) provides new insights into the regulatory function of decidual macrophages in pregnancy that may have implications in pregnancy complications. Conclusions/Significance: The molecular characterization of decidual macrophages presents a unique transcriptional profile replete with important components for fetal immunoprotection and provides several clues for further studies of these cells.
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| 5. |
- Kruse, Bastian, et al.
(författare)
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CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours
- 2023
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 618:7967, s. 1033-1040
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Tidskriftsartikel (refereegranskat)abstract
- Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T cells to directly recognize and kill tumour cells1,2,3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4,5,6. The ability of CD4+ effector cells to contribute to antitumour immunity independently of CD8+ T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified7,8,9,10. Here, we describe a mechanism whereby a small number of CD4+ T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8+ T cell targeting. The CD4+ effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II+CD11c+ antigen-presenting cells. We show that T helper type 1 cell-directed CD4+ T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4+ T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4+ T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8+ T cells and natural killer cells and advance cancer immunotherapies.
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| 6. |
- Quentmeier, Hilmar, et al.
(författare)
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FOXR1 Activation in B-Cell Lymphoma
- 2015
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Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 126:23
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 7. |
- Quentmeier, Hilmar, et al.
(författare)
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Subclones in B-lymphoma cell lines: isogenic models for the studyof gene regulation
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:39, s. 63456-63465
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Tidskriftsartikel (refereegranskat)abstract
- Genetic heterogeneity though common in tumors has been rarely documented in celllines. To examine how often B-lymphoma cell lines are comprised of subclones, weperformed immunoglobulin (IG) heavy chain hypermutation analysis. Revealing thatsubclones are not rare in B-cell lymphoma cell lines, 6/49 IG hypermutated cell lines(12%) consisted of subclones with individual IG mutations. Subclones were alsoidentified in 2/284 leukemia/lymphoma cell lines exhibiting bimodal CD markerexpression. We successfully isolated 10 subclones from four cell lines (HG3, SUDHL-5, TMD-8, U-2932). Whole exome sequencing was performed to molecularlycharacterize these subclones. We describe in detail the clonal structure of cell lineHG3, derived from chronic lymphocytic leukemia. HG3 consists of three subcloneseach bearing clone-specific aberrations, gene expression and DNA methylationpatterns. While donor patient leukemic cells were CD5+, two of three HG3 subcloneshad independently lost this marker. CD5 on HG3 cells was regulated byepigenetic/transcriptional mechanisms rather than by alternative splicing as reportedhitherto. In conclusion, we show that the presence of subclones in cell lines carryingindividual mutations and characterized by sets of differentially expressed genes is notuncommon. We show also that these subclones can be useful isogenic models forregulatory and functional studies.
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| 8. |
- Seifert (Bock), Oliver, et al.
(författare)
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Identification of unique gene expression patterns within different lesional sites of keloids
- 2008
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Ingår i: Wound Repair and Regeneration. - 1067-1927 .- 1524-475X. ; 16:2, s. 254-265
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Tidskriftsartikel (refereegranskat)abstract
- Keloid disease is a significant clinical problem, especially in black populations, with an estimated incidence of 4–16%. Keloids are fibroproliferative dermal tumors developing as a result of deregulated wound healing. The dynamic nature of keloids is illustrated by clinical regression in the center, while the margin remains active growing into the surrounding healthy skin. Therefore, the gene expression profiles of fibroblasts from different sites of the keloids were characterized using Affymetrix microarrays covering the whole human genome. This study revealed 105 genes that were differentially regulated (79 genes were up-regulated and 26 down-regulated) in a unique gene expression profile in different sites of keloids where progression or regression of the process was in progress. The apoptosis inhibitor AVEN was found to be up-regulated at the active margin of keloids, while apoptosis-inducing genes such as ADAM12 and genes inducing extracellular matrix (ECM) degradation such as matrix metalloproteinase-19 were up-regulated in the regressing keloid center. We identified genes previously not described in the development of keloids. Activating proapoptotic genes or inhibiting ECM-inducing genes as INHBA or monocyte chemoattractant protein-1 might be possible target genes for new treatment strategies for keloid disease.
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| 9. |
- Seifert, Oliver, et al.
(författare)
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Gene expression profiling of macrophages: implications for an immunosuppressive effect of dissolucytotic gold ions
- 2012
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Ingår i: Journal of Inflammation. - : BioMed Central. - 1476-9255. ; 9:43
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gold salts has previously been used in the treatment of rheumatoid arthritis but have been replaced by biologicals such as TNF-alpha inhibitors. The mechanisms behind the anti-inflammatory effect of metallic gold ions are still unknown, however, recent data showed that charged gold atoms are released from pure metallic gold implants by macrophages via a dissolucytosis membrane, and that gold ions are taken up by local macrophages, mast cells and to some extent fibroblasts. These findings open the question of possible immunomodulatory effects of metallic gold and motivate efforts on a deeper understanding of the effect of metallic gold on key inflammatory cells as macrophages. less thanbrgreater than less thanbrgreater thanMethods: Human macrophage cells (cell line THP-1) were grown on gold foils and intracellular uptake was analysed by autometallography. The impact of phagocytised gold ions on viability of THP-1 cells was investigated by trypan blue staining and TUNEL assay. The global gene expression profile of THP-1 cells after incorporation of gold ions was studied using microarray analysis comprising approximately 20,000 genes. The gene expression data was confirmed by measurement of secreted proteins. less thanbrgreater than less thanbrgreater thanResults: Autometallography showed intracellular uptake of gold ions into THP-1 cells. No significant effect on viability of THP-1 cells was demonstrated. Our data revealed a unique gene expression signature of dissolucytotic THP-1 cells that had taken up gold ions. A large number of regulated genes were functionally related to immunomodulation. Gold ion uptake induced downregulation of genes involved in rheumatoid arthritis such as hepatocyte growth factor, tenascin-C, inhibitor of DNA binding 1 and 3 and matrix metalloproteinase 13. less thanbrgreater than less thanbrgreater thanConclusion: The data obtained in this study offer new insights into the mode of action of gold ions and suggest for the investigation of effects on other key cells and a possible future role of metallic gold as implants in rheumatoid arthritis or other inflammatory conditions.
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| 10. |
- Slind Olsen, Renate, et al.
(författare)
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Possible role and therapeutic target of PDGF-D signalling in colorectal cancer
- 2019
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Ingår i: Cancer Investigation. - : Taylor & Francis. - 0735-7907 .- 1532-4192. ; 37:2, s. 99-112
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor D (PDGF-D) has been shown to mediate cellular processes of importance in cancer progression. This study aimed to investigate the expression and putative involvement of PDGF-D signaling in colorectal carcinogenesis. PDGF-D was expressed in vascular endothelial cells in tumor and normal tissues. PDGF-D stimulation of cells altered genes of importance in carcinogenic processes. In addition, PDGF-D increased the proliferation rate while imatinib inhibited these effects. PDGF-D and its PDGF receptor beta (PDGFR-β) are expressed in colorectal cancer and blockage of PDGF-D/PDGFR-β signaling using tyrosine kinase inhibitors, such as imatinib, might be important in inhibiting tumor-promoting actions.
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| 11. |
- Stark, Lisa, et al.
(författare)
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Staphylococcus aureus isolates from blood and anterior nares induce similar innate immune responses in endothelial cells
- 2009
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Ingår i: APMIS. - : Wiley. - 0903-4641 .- 1600-0463 .- 0903-465X .- 1600-5503. ; 117:11, s. 814-824
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the possibility to distinguish virulent from non-virulent isolates, gene expression in human umbilical vein endothelial cells (HUVEC) induced by invasive and colonizing isolates of Staphylococcus aureus was compared. Gene expression in HUVEC was analyzed by microarray analysis after 4 h of infection with Staphylococcus aureus, isolated from healthy nasal carriers (n = 5) and from blood of septic patients (n = 5), to explore possible differences between the groups of bacteria in interaction with HUVEC. All isolates were spa-typed to disclose strain relatedness. Moreover, the isolates were characterized with DNA microarray to determine the presence of virulence genes and to investigate the potential genes of importance in HUVEC interaction. The expression of 41 genes was up-regulated, and four were down-regulated in HUVEC by all isolates. Most of the up-regulated genes encode cytokines, chemokines, interferon-induced proteins, proteins regulating apoptosis and cell proliferation. There was no difference in the gene expression pattern between HUVEC infected with invasive or colonizing isolates. Furthermore, there was no difference in the presence of bacterial virulence genes between the two groups. In conclusion, our data indicate that S. aureus isolates induce comparable expression patterns in HUVEC, irrespective of invasiveness or presence of virulence genes.
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| 12. |
- Sundarasetty, Bala Sai, et al.
(författare)
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Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1(+) Acute Myeloid Leukemia
- 2013
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Ingår i: Human Gene Therapy. - : Mary Ann Liebert Inc. - 1043-0342 .- 1557-7422. ; 24:2, s. 220-237
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Tidskriftsartikel (refereegranskat)abstract
- Wilms' tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML), a high-risk neoplasm warranting development of novel immunotherapeutic approaches. Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. With the rationale of stimulating multiantigenic responses against WT1, we genetically programmed long-lasting dendritic cells capable of producing and processing endogenous WT1 epitopes. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-4 (IL-4) was used to transduce human monocytes ex vivo. Overnight transduction induced self-differentiation of monocytes into immunophenotypically stable "SmartDC/tWT1" (GM-CSF+, IL-4(+), tWT1(+), IL-6(+), IL-8(+), TNF-alpha(+), MCP-1(+), HLA-DR+, CD86(+), CCR2(+), CCR5(+)) that were viable for 3 weeks in vitro. SmartDC/tWT1 were produced with peripheral blood mononuclear cells (PBMC) obtained from an FLT3-ITD+ AML patient and surplus material from a donor lymphocyte infusion (DLI) and used to expand CD8(+) T cells in vitro. Expanded cytotoxic T lymphocytes (CTLs) showed antigen-specific reactivity against WT1 and against WT1(+) leukemia cells. SmartDC/tWT1 injected s.c. into Nod.Rag1(-/-).IL2r gamma c(-/-) mice were viable in vivo for more than three weeks. Migration of human T cells (huCTLs) to the immunization site was demonstrated following adoptive transfer of huCTLs into mice immunized with SmartDC/tWT1. Furthermore, SmartDC/tWT1 immunization plus adoptive transfer of T cells reactive against WT1 into mice resulted in growth arrest of a WT1(+) tumor. Gene array analyses of SmartDC/tWT1 demonstrated upregulation of several genes related to innate immunity. Thus, SmartDC/tWT1 can be produced in a single day of ex vivo gene transfer, are highly viable in vivo, and have great potential for use as immunotherapy against malignant transformation overexpressing WT1.
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| 13. |
- Svensson-Arvelund, Judit, 1982-, et al.
(författare)
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Decidual macrophages contribute to the unique leukocyte composition at the fetal-maternal interface by production of IL-35, induction of Treg cells and production of homeostatic chemokines
- 2015
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Reproductive success depends on the ability of the maternal immune system to adapt in order to tolerate and support the growing semi-allogenic fetus. Macrophages, being a major leukocyte population in the uterine mucosa (decidua), may play a central role in promoting the unique composition and regulatory phenotype of leukocytes that is characteristic for the fetal-maternal interface. We show that decidual macrophages display a predominantly immune regulatory gene profile and produce the immunosuppressive cytokine IL-35 but no other members of the IL-12 family (IL-12, IL-23 and IL-27). Decidual macrophages also promoted the selective expansion of CD25highFoxp3+ Tregs but not of Tbet+ Th1, GATA-3+ Th2 and Rorγt+ Th17 cells. In addition, these macrophages preferentially secreted the monocyte- and Treg-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. Among in vitro macrophages, distinct chemokine profiles were observed; IL-4/13 upregulated Th2-associated chemokines (CCL17, CCL22, CCL26) while LPS/IFNγ upregulated Th1-associated chemokines (CXCL9, CXCL10, CXCL11, CCL5). M(IL-10) macrophages (induced by M-CSF and IL-10) showed a chemokine profile similar to that of decidual macrophages, as shown by gene expression and protein analysis. By using M(IL-10) macrophages as a model of decidual macrophages, we show that these cells promote the recruitment of CD14+ monocytes, while migration of several lymphocyte populations was unaltered or prevented. These data implicate decidual macrophages as critical regulators of the decidual leukocyte composition and phenotype that is associated with successful reproduction.
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| 14. |
- Svensson, Judit, et al.
(författare)
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Gene expression and protein secretion patterns in decidual macrophages and different M1 and M2 macrophage populations with focus on M-CSF and IL-10 as polarising factors in JOURNAL OF REPRODUCTIVE IMMUNOLOGY, vol 90, issue 2, pp 151-151
- 2011
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Ingår i: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 90:2, s. 151-151
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We have recently observed (Svensson et al., data to be published) that M-CSF and IL-10, among several factors tested, are able to induce macrophages (MΦ) with phenotypic characteristics of decidual MΦ with expression of typical M2, or immune regulatory, cell surface markers (scavenger receptor, mannose receptor, DC-SIGN). The aim of this study was to investigate in a comprehensive manner whether this finding could be shown by an extended mapping of secreted molecules and also at the gene expression level.Materials and methods: CD14+ blood monocytes and decidual MΦ from healthy first trimester pregnant women (n = 11) were isolated by immunomagnetic cell sorting (MACS). MΦ were also generated in vitro from MACS-sorted CD14+ blood monocytes from non-pregnant women. RNA was isolated from blood monocytes and MΦ and the expression of 100 decidual MΦ-associated genes (Gustafsson et al., PlosOne 2008) was analysed with a custom microarray. RT-PCR was used to analyse the gene expression of IRF5, which was recently associated with classically activated (M1) MΦ. A multiplex bead assay was used to quantify the levels of cytokines and chemokines in conditioned media.Results: To estimate the similarity of the in vitro differentiated MΦ with decidual MΦ, we performed hierarchical clustering of differentially regulated genes. M1 MΦ and MΦ treated with GM-CSF and IL-4/13 formed their own branches, indicating transcriptional profiles clearly differing from all other MΦ types analysed. MΦ differentiated with M-CSF alone or with IL-10, regardless of the growth factor used, clustered together with decidual MΦ, supporting their close relationship. Genes similarly regulated in these macrophages were not restricted to immune modulating genes. This group included the M2-associated chemokines CCL2 and CCL18, the immune modulating B7 family-related VSIG4, the angiogenic insulin-like growth factor-1 and the M2-associated folate receptor β-encoding FOLR2 and selenoprotein-encoding SEPP1. The M2 polarisation status of decidual MΦ was confirmed by low expression of the M1-associated transcription factor IRF5, and comparable levels were detected in M-CSF- and IL-10-stimulated MΦ. IRF5 expression was higher in M1 MΦ and, surprisingly, also in IL-4/13-stimulated MΦ. As to protein secretion, decidual and M-CSF/IL-10-stimulated MΦ were found to produce comparable levels of IL-10 and the pro-inflammatory cytokines IL-6 and TNF, while M1 MΦ produced significantly higher levels of TNF and did not produce IL-10. Decidual and M-CSF/IL-10-stimulated MΦ also produced high levels of the monocyte- and granulocyte-recruiting chemokines CCL2, CCL4 and CXCL1, while the Th1 cell-recruiting CXCL10 and the Th2 cell-recruiting CCL22 were only produced at low levels. CXCL10 was highest in M1 MΦ, while CCL22 levels were highest in GM-CSF and/or IL-4/13-stimulated MΦ.Conclusions: Our data consistently shows a central role for M-CSF and IL-10 as polarising agents for decidual MΦ, while Th2 and pro-inflammatory agents induce MΦ with clearly differing characteristics. We hypothesise that decidual MΦ have a predominant homeostatic function. This is supported by their low production of both Th1 and Th2 cell-recruiting chemokines. It is thus likely that M-CSF and IL-10 shape the polarisation of decidual MΦ contributing to the homeostatic and tolerant immune environment required for successful fetal development.
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| 15. |
- Svensson, Judit, et al.
(författare)
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Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M-CSF and IL-10
- 2011
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 187:7, s. 3671-3682
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Tidskriftsartikel (refereegranskat)abstract
- During pregnancy, the maternal immune system is challenged by the presence of the fetus, which must be tolerated despite being semiallogeneic. Uterine mucosal (or decidual) macrophages (Mϕ), one of the major leukocyte populations at the fetal–maternal interface, have been implicated in fetal tolerance, but information regarding their regulation is scarce. In this study, we investigated the role of several factors potentially involved in the differentiation and polarization of decidual Mϕ with an in vitro Mϕ differentiation model. By using flow cytometry, we showed that M-CSF and IL-10 were potent inducers of M2 (immunoregulatory) Mϕ markers expressed on human decidual Mϕ (CD14, CD163, CD206, CD209). In contrast, proinflammatory stimuli, and unexpectedly also the Th2-associated IL-4 and IL-13, induced different patterns of expression, indicating that a Th2-dominated environment is not required for decidual Mϕ polarization. M-CSF/IL-10–stimulated and decidual Mϕ also showed similar cytokine secretion patterns, with production of IL-10 as well as IL-6, TNF, and CCL4. Conversely, the proinflammatory, LPS/IFN-γ–stimulated Mϕ produced significantly higher levels of TNF and no IL-10. We also used a gene array with 420 Mϕ-related genes, of which 100 were previously reported to be regulated in a global gene expression profiling of decidual Mϕ, confirming that M-CSF/IL-10–induced Mϕ are closely related to decidual Mϕ. Taken together, our results consistently point to a central role for M-CSF and in particular IL-10 in the shaping of decidual Mϕ with regulatory properties. These cytokines may therefore play an important role in supporting the homeostatic and tolerant immune milieu required for a successful pregnancy.
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