scholarly journals Dimethyl fumarate suppresses granulocyte macrophage colony-stimulating factor–producing Th1 cells in CNS neuroinflammation

2020 ◽  
Vol 7 (4) ◽  
pp. e729 ◽  
Author(s):  
Farinaz Safavi ◽  
Rodolfo Thome ◽  
Zichen Li ◽  
Guang-Xian Zhang ◽  
Abdolmohamad Rostami
Keyword(s):  
T Cells ◽  
Dimethyl Fumarate ◽  
Th1 Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Healthy Donors ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor

ObjectiveTo study the immunomodulatory effect of dimethyl fumarate (DF) on granulocyte macrophage colony-stimulating factor (GM-CSF) production in CD4+ T cells in experimental autoimmune encephalomyelitis (EAE) and human peripheral blood mononuclear cells (PBMCs).MethodsWe collected splenocytes and CD4+ T cells from C57BL/6 wild-type and interferon (IFN)-γ–deficient mice. For human PBMCs, venous blood was collected from healthy donors, and PBMCs were collected using the Percoll gradient method. Cells were cultured with anti-CD3/28 in the presence/absence of DF for 3 to 5 days. Cells were stained and analyzed by flow cytometry. Cytokines were measured by ELISA in cell supernatants. For in vivo experiments, EAE was induced by myelin oligodendrocyte glycoprotein35–55 and mice were treated with oral DF or vehicle daily.ResultsDF acts directly on CD4+ T cells and suppresses GM-CSF–producing Th1 not Th17 or single GM-CSF+ T cells in EAE. In addition, GM-CSF suppression depends on the IFN-γ pathway. We also show that DF specifically suppresses Th1 and GM-CSF–producing Th1 cells in PBMCs from healthy donors.ConclusionsWe suggest that DF exclusively suppresses GM-CSF–producing Th1 cells in both animal and human CD4+ T cells through an IFN-γ–dependent pathway. These findings indicate that DF has a better therapeutic effect on patients with Th1-dominant immunophenotype. However, future longitudinal study to validate this finding in MS is needed.

scholarly journals Interferon γ–independent Rejection of Interleukin 12–transduced Carcinoma Cells Requires CD4+ T Cells and Granulocyte/Macrophage Colony–stimulating Factor

1998 ◽  
Vol 188 (1) ◽  
pp. 133-143 ◽  
Author(s):  
Chiara Zilocchi ◽  
Antonella Stoppacciaro ◽  
Claudia Chiodoni ◽  
Mariella Parenza ◽  
Nadia Terrazzini ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Regression ◽  
Tumor Rejection ◽  
Interleukin 12 ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor

We analyzed the ability of interferon (IFN)-γ knockout mice (GKO) to reject a colon carcinoma transduced with interleukin (IL)-12 genes (C26/IL-12). Although the absence of IFN-γ impaired the early response and reduced the time to tumor onset in GKO mice, the overall tumor take rate was similar to that of BALB/c mice. In GKO mice, C26/IL-12 tumors had a reduced number of infiltrating leukocytes, especially CD8 and natural killer cells. Analysis of the tumor site, draining nodes, and spleens of GKO mice revealed reduced expression of IFN- inducible protein 10 and monokine induced by γ-IFN. Despite these defects, GKO mice that rejected C26/IL-12 tumor, and mice that were primed in vivo with irradiated C26/IL-12 cells, showed the same cytotoxic T lymphocyte activity but higher production of granulocyte/macrophage colony–stimulating factor (GM-CSF) as compared with control BALB/c mice. Treatment with monoclonal antibodies against GM-CSF abrogated tumor regression in GKO but not in BALB/c mice. CD4 T lymphocytes, which proved unnecessary or suppressive during rejection of C26/IL-12 cells in BALB/c mice, were required for tumor rejection in GKO mice. CD4 T cell depletion was coupled with a decline in GM-CSF expression by lymphocytes infiltrating the tumors or in the draining nodes, and with the reduction and disappearance of granulocytes and CD8 T cells, respectively, in tumor nodules. These results suggest that GM-CSF can substitute for IFN-γ in maintaining the CD8–polymorphonuclear leukocyte cross-talk that is a hallmark of tumor rejection.

scholarly journals Granulocyte-Macrophage Colony-Stimulating Factor-Deficient Mice Have Impaired Resistance to Blood-Stage Malaria

2001 ◽  
Vol 69 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Julie Riopel ◽  
MiFong Tam ◽  
Karkada Mohan ◽  
Michael W. Marino ◽  
Mary M. Stevenson
Keyword(s):  
Blood Stage ◽  
Colony Stimulating Factor ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Tnf Α ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Blood Stage Malaria

ABSTRACT The contribution of granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic and immunoregulatory cytokine, to resistance to blood-stage malaria was investigated by infecting GM-CSF-deficient (knockout [KO]) mice with Plasmodium chabaudi AS. KO mice were more susceptible to infection than wild-type (WT) mice, as evidenced by higher peak parasitemia, recurrent recrudescent parasitemia, and high mortality. P. chabaudiAS-infected KO mice had impaired splenomegaly and lower leukocytosis but equivalent levels of anemia compared to infected WT mice. Both bone marrow and splenic erythropoiesis were normal in infected KO mice. However, granulocyte-macrophage colony formation was significantly decreased in these tissues of uninfected and infected KO mice, and the numbers of macrophages in the spleen and peritoneal cavity were significantly lower than in infected WT mice. Serum levels of gamma interferon (IFN-γ) were found to be significantly higher in uninfected KO mice, and the level of this cytokine was not increased during infection. In contrast, IFN-γ levels were significantly above normal levels in infected WT mice. During infection, tumor necrosis factor alpha (TNF-α) levels were significantly increased in KO mice and were significantly higher than TNF-α levels in infected WT mice. Our results indicate that GM-CSF contributes to resistance to P. chabaudi AS infection and that it is involved in the development of splenomegaly, leukocytosis, and granulocyte-macrophage hematopoiesis. GM-CSF may also regulate IFN-γ and TNF-α production and activity in response to infection. The abnormal responses seen in infected KO mice may be due to the lack of GM-CSF during development, to the lack of GM-CSF in the infected mature mice, or to both.

scholarly journals NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene.

1990 ◽  
Vol 10 (3) ◽  
pp. 1281-1286 ◽  
Author(s):  
R Schreck ◽  
P A Baeuerle
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Interleukin 2 ◽  
Colony Stimulating Factor ◽  
Nf Kappa B ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The expression of the gene encoding the granulocyte-macrophage colony-stimulating factor (GM-CSF) is induced upon activation of T cells with phytohemagglutinin and active phorbolester and upon expression of tax1, a transactivating protein of the human T-cell leukemia virus type I. The same agents induce transcription from the interleukin-2 receptor alpha-chain and interleukin-2 genes, depending on promoter elements that bind the inducible transcription factor NF-kappa B (or an NF-kappa B-like factor). We therefore tested the possibility that the GM-CSF gene is also regulated by a cognate motif for the NF-kappa B transcription factor. A recent functional analysis by Miyatake et al. (S. Miyatake, M. Seiki, M. Yoshida, and K. Arai, Mol. Cell. Biol. 8:5581-5587, 1988) described a short promoter region in the GM-CSF gene that conferred strong inducibility by T-cell-activating signals and tax1, but no NF-kappa B-binding motifs were identified. Using electrophoretic mobility shift assays, we showed binding of purified human NF-kappa B and of the NF-kappa B activated in Jurkat T cells to an oligonucleotide comprising the GM-CSF promoter element responsible for mediating responsiveness to T-cell-activating signals and tax1. As shown by a methylation interference analysis and oligonucleotide competition experiments, purified NF-kappa B binds at positions -82 to -91 (GGGAACTACC) of the GM-CSF promoter sequence with an affinity similar to that with which it binds to the biologically functional kappa B motif in the beta interferon promoter (GGGAAATTCC). Two kappa B-like motifs at positions -98 to -108 of the GM-CSF promoter were also recognized but with much lower affinities. Our data provide strong evidence that the expression of the GM-CSF gene following T-cell activation is controlled by binding of the NF-kappa B transcription factor to a high-affinity binding site in the GM-CSF promoter.

scholarly journals Expression of the macrophage-specific colony-stimulating factor in human monocytes treated with granulocyte-macrophage colony-stimulating factor

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1259-1261
Author(s):  
J Horiguchi ◽  
MK Warren ◽  
D Kufe
Keyword(s):  
T Cells ◽  
Gene Product ◽  
Phorbol Ester ◽  
Human Monocytes ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Activated Monocytes ◽  
Macrophage Colony ◽  
Stimulating Factor

The macrophage-specific colony-stimulating factor (CSF-1, M-CSF) regulates the survival, growth and differentiation of monocytes. We have recently demonstrated that phorbol ester induces expression of CSF- 1 in human monocytes. These findings suggested that activated monocytes are capable of producing their own lineage-specific CSF. The present studies demonstrate that the granulocyte-macrophage colony-stimulating factor (GM-CSF) also induces CSF-1 transcripts in monocytes. Furthermore, we demonstrate that the detection of CSF-1 RNA in GM-CSF- treated monocytes is associated with synthesis of the CSF-1 gene product. The results thus suggest that GM-CSF may indirectly control specific monocyte functions through the regulation of CSF-1 production. These findings indicate another level of interaction between T cells and monocytes.

scholarly journals Differentiation of human dendritic cells from monocytes in vitro using granulocyte-macrophage colony stimulating factor and low concentration of interleukin-4

2003 ◽  
Vol 60 (5) ◽  
pp. 531-538 ◽  
Author(s):  
Miodrag Colic ◽  
Dusan Jandric ◽  
Zorica Stojic-Vukanic ◽  
Jelena Antic-Stankovic ◽  
Petar Popovic ◽  
...  
Keyword(s):  
T Cells ◽  
Interleukin 4 ◽  
Adherent Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Alloreactive T Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Human Dendritic Cells ◽  
Stimulating Factor

Several laboratories have developed culture systems that allow the generation of large numbers of human dendritic cells (DC) from monocytes using granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-4 (IL-4). In this work we provided evidence that GM-CSF (100 ng/ml) in combination with a low concentration of IL-4 (5 ng/ml) was efficient in the generation of immature, non-adherent, monocyte-derived DC as the same concentration of GM-CSF, and ten times higher concentration of IL-4 (50 ng/ml). This conclusion was based on the similar phenotype profile of DC such as the expression of CD1a, CD80, CD86, and HLA-DR, down-regulation of CD14, and the absence of CD83, as well as on their similar allostimulatory activity for T cells. A higher number of cells remained adherent in cultures with lower concentrations of IL-4 than in cultures with higher concentrations of the cytokine. However, most of these adherent cells down-regulated CD14 and stimulated the proliferation of alloreactive T cells. In contrast adherent cells cultivated with GM-CSF alone were predominantly macrophages as judged by the expression of CD14 and the inefficiency to stimulate alloreactive T cells. DC generated in the presence of lower concentrations of IL-4 had higher proapoptotic potential for the Jurkat cell line than DC differentiated with higher concentrations of IL-4, suggesting their stronger cytotoxic, anti-tumor effect.

Interferon-γ switches monocyte differentiation from dendritic cells to macrophages

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Yves Delneste ◽  
Peggy Charbonnier ◽  
Nathalie Herbault ◽  
Giovanni Magistrelli ◽  
Gersende Caron ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Interferon Γ ◽  
Transcriptional Level ◽  
Colony Stimulating Factor ◽  
Monocyte Differentiation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Human monocytes differentiate into dendritic cells (DCs) or macrophages according to the nature of environmental signals. Monocytes stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin 4 (IL-4) yield DCs. We tested here whether interferon-γ (IFN-γ), a potent activator of macrophages, may modulate monocyte differentiation. Addition of IFN-γ to IL-4 plus GM-CSF–stimulated monocytes switches their differentiation from DCs to CD14−CD64+ macrophages. IFN-γ increases macrophage colony-stimulating factor (M-CSF) and IL-6 production by IL-4 plus GM-CSF–stimulated monocytes by acting at the transcriptional level and acts together with IL-4 to up-regulate M-CSF but not IL-6 production. IFN-γ also increases M-CSF receptor internalization. Results from neutralizing experiments show that both M-CSF and IL-6 are involved in the ability of IFN-γ to skew monocyte differentiation from DCs to macrophages. Finally, this effect of IFN-γ is limited to early stages of differentiation. When added to immature DCs, IFN-γ up-regulates IL-6 but not M-CSF production and does not convert them to macrophages, even in the presence of exogenous M-CSF. In conclusion, IFN-γ shifts monocyte differentiation to macrophages rather than DCs through autocrine M-CSF and IL-6 production. These data show that IFN-γ controls the differentiation of antigen-presenting cells and thereby reveals a new mechanism by which IFN-γ orchestrates the outcome of specific immune responses.

scholarly journals Granulocyte-macrophage colony-stimulating factor augmentation of T-cell receptor-dependent and T-cell receptor-independent thymocyte proliferation

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 713-723
Author(s):  
AM Stewart-Akers ◽  
JS Cairns ◽  
DJ Tweardy ◽  
SA McCarthy
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Thymocyte Proliferation ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The effects of granulocyte-macrophage colony-stimulating factor (GM- CSF) are not confined to cells of the myeloid lineage. GM-CSF has been shown to have effects on mature T cells and both mature and immature T- cell lines. We therefore examined the GM-CSF responsiveness of murine thymocytes to investigate whether GM-CSF also affected normal immature T lymphocytes. The studies presented here indicate that GM-CSF augments accessory cell (AC)-dependent T-cell receptor (TCR)-mediated proliferation of unseparated thymocyte populations. To identify the GM- CSF responsive cell type, thymic AC and T cells were examined for GM- CSF responsiveness. We found that GM-CSF augmentation of TCR-induced thymocyte proliferation appears to be mediated via augmentation of AC function, and not via direct effects on mature single-positive (SP) thymocytes. Enriched double-negative (DN) thymocytes were also tested for GM-CSF responsiveness. GM-CSF induced the proliferation of adult and fetal DN thymocytes in an AC-independent and TCR-independent single- cell assay. Thus, in contrast to the SP thymocytes, a DN thymocyte population was directly responsive to GM-CSF. GM-CSF therefore may play a direct role in the expansion of DN thymocytes and an indirect role in the expansion of SP thymocytes.

scholarly journals Expression of the macrophage-specific colony-stimulating factor in human monocytes treated with granulocyte-macrophage colony-stimulating factor

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1259-1261 ◽  
Author(s):  
J Horiguchi ◽  
MK Warren ◽  
D Kufe
Keyword(s):  
T Cells ◽  
Gene Product ◽  
Phorbol Ester ◽  
Human Monocytes ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Activated Monocytes ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The macrophage-specific colony-stimulating factor (CSF-1, M-CSF) regulates the survival, growth and differentiation of monocytes. We have recently demonstrated that phorbol ester induces expression of CSF- 1 in human monocytes. These findings suggested that activated monocytes are capable of producing their own lineage-specific CSF. The present studies demonstrate that the granulocyte-macrophage colony-stimulating factor (GM-CSF) also induces CSF-1 transcripts in monocytes. Furthermore, we demonstrate that the detection of CSF-1 RNA in GM-CSF- treated monocytes is associated with synthesis of the CSF-1 gene product. The results thus suggest that GM-CSF may indirectly control specific monocyte functions through the regulation of CSF-1 production. These findings indicate another level of interaction between T cells and monocytes.

scholarly journals CXC chemokine receptor 3 expression on CD34+hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor: chemotaxis and adhesion induced by its ligands, interferon γ–inducible protein 10 and monokine induced by interferon γ

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1230-1238 ◽  
Author(s):  
Tan Jinquan ◽  
Sha Quan ◽  
Henrik H. Jacobi ◽  
Chen Jing ◽  
Anders Millner ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Colony Stimulating Factor ◽  
Hematopoietic Progenitors ◽  
Human Cord Blood ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Inducible Protein ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract CXC chemokine receptor 3 (CXCR3), which is known to be expressed predominately on memory and activated T lymphocytes, is a receptor for both interferon γ (IFN-γ)–inducible protein 10 (γIP-10) and monokine induced by IFN-γ (Mig). We report the novel finding that CXCR3 is also expressed on CD34+ hematopoietic progenitors from human cord blood stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) but not on freshly isolated CD34+ progenitors. Freshly isolated CD34+progenitors expressed low levels of CXCR3 messenger RNA, but this expression was highly up-regulated by GM-CSF, as indicated by a real-time quantitative reverse transcriptase–polymerase chain reaction technique. γIP-10 and Mig induced chemotaxis of GM-CSF–stimulated CD34+ progenitors by means of CXCR3, since an anti-CXCR3 monoclonal antibody (mAb) was found to block γIP-10–induced and Mig-induced CD34+ progenitor chemotaxis. These chemotactic attracted CD34+ progenitors are colony-forming units—granulocyte-macrophage. γIP-10 and Mig also induced GM-CSF–stimulated CD34+ progenitor adhesion and aggregation by means of CXCR3, a finding confirmed by the observation that anti-CXCR3 mAb blocked these functions of γIP-10 and Mig but not of chemokine stromal cell–derived factor 1α. γIP-10–induced and Mig-induced up-regulation of integrins (CD49a and CD49b) was found to play a crucial role in adhesion of GM-CSF–stimulated CD34+progenitors. Moreover, γIP-10 and Mig stimulated CXCR3 redistribution and cellular polarization in GM-CSF–stimulated CD34+progenitors. These results indicate that CXCR3–γIP-10 and CXCR3–Mig receptor-ligand pairs, as well as the effects of GM-CSF on them, may be especially important in the cytokine/chemokine environment for the physiologic and pathophysiologic events of differentiation of CD34+ hematopoietic progenitors into lymphoid and myeloid stem cells, subsequently immune and inflammatory cells. These processes include transmigration, relocation, differentiation, and maturation of CD34+ hematopoietic progenitors.

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