scholarly journals The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation

2016 ◽  
Vol 213 (4) ◽  
pp. 585-603 ◽  
Author(s):  
David Langlais ◽  
Luis B. Barreiro ◽  
Philippe Gros
Keyword(s):  
Pulmonary Tuberculosis ◽  
Mouse Models ◽  
Chromatin Immunoprecipitation ◽  
Inflammatory Diseases ◽  
Transcriptional Regulators ◽  
Interferon Γ ◽  
Wild Type ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Ifn Γ ◽  
And Function

IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by proinflammatory signals such as interferon-γ (IFN-γ). Loss of IRF8 or IRF1 function causes severe susceptibility to infections in mice and in humans. We used chromatin immunoprecipitation sequencing and RNA sequencing in wild type and in IRF8 and IRF1 mutant primary macrophages to systematically catalog all of the genes bound by (cistromes) and transcriptionally activated by (regulomes) IRF8, IRF1, PU.1, and STAT1, including modulation of epigenetic histone marks. Of the seven binding combinations identified, two (cluster 1 [IRF8/IRF1/STAT1/PU.1] and cluster 5 [IRF1/STAT1/PU.1]) were found to have a major role in controlling macrophage transcriptional programs both at the basal level and after IFN-γ activation. They direct the expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and antimicrobial defenses in mouse models of neuroinflammation and of pulmonary tuberculosis, respectively. In addition, this IRF8/IRF1 regulome is enriched for genes mutated in human primary immunodeficiencies and with loci associated with several inflammatory diseases in humans.

scholarly journals KORELASI KADAR SERUM IFN-γ, EKSPRESI DAN FUNGSI RESEPTOR IFN-γ, DENGAN KEJADIAN TUBERKULOSIS PARU (The Correlation Of Ifn-γ Serum Level, Ifn-γ Receptor Expression And Function, With Pulmonary Tuberculosis)

2013 ◽  
Vol 3 (3) ◽  
Author(s):  
Jahja Teguh Widjaja
Keyword(s):  
Stem Cell ◽  
Serum Level ◽  
Pulmonary Tuberculosis ◽  
Mononuclear Cells ◽  
Receptor Expression ◽  
Cross Sectional ◽  
Tuberculosis Patients ◽  
Ifn Γ ◽  
Cross Sectional Design ◽  
And Function

AbstrakUntuk dapat bekerja dengan efektif menghadapi M. tuberculosis, sistim imunitas seluler memerlukan kadar IFN-γ dan reseptor IFN-γ di sel-sel mononuklear yang bekerja optimal. Tujuan penelitian ini adalah menganalisis korelasi antara kadar serum IFN-, ekspresi dan fungsi reseptor IFN-γ, dengan kejadian penyakit Tuberkulosis Paru. Observasi analitik dengan rancangan potong silang yang membandingkan kadar serum IFN-γ, fungsi dan ekspresi reseptor IFN-γ, pada pasien TB Paru dengan pasangannya yang sehat, serta menganalisis korelasi antara variabel-variabel tersebut dengan kejadian penyakit TB Paru. Penelitian dilakukan pada Juli 2009 sampai September 2010, di RS Immanuel Bandung dan laboratorium Stem Cell & Cancer Institute, Jakarta. Dibandingkan pasangan hidupnya, kadar serum IFN-γ pasien TB tidak berbeda bermakna, ekspresi reseptor IFN-γ pasien TB lebih tinggi (p=0,041), sedangkan fungsi reseptor IFN-γ pasien TB lebih rendah (p=0,011). Analisis korelasi mendapatkan satusatunya variabel yang mempunyai korelasi bermakna dengan kejadian tuberkulosis paru adalah fungsi reseptor IFN-γ yang rendah (p=0,026, OR 5,56). Pada pasien TB Paru ekspresi reseptor IFN-γ lebih tinggi, tetapi fungsi reseptor IFN-γ lebih rendah dari pasangan hidup sehat. Fungsi reseptor IFN-γ yang rendah ini mempunyai korelasi bermakna dengan kejadian tuberkulosis paru.Kata kunci: tuberkulosis, kadar serum IFN-γ, ekspresi dan fungsi reseptor IFN-γ.AbstractIn order to work effectively against M. tuberculosis, the cell mediated immune system needs serum level of IFN-γ and its receptors in the surface of mononuclear cells to function optimally. The objective of this study is to analyze the correlation of IFNγ serum level, expression and function of IFN-γ receptor, with pulmonary tuberculosis. Analytical descriptive method with cross sectional design that compared the serum level of IFN-γ, function and expression of IFN-γ receptor in pulmonary tuberculosis patients with their healthy spouses, and analyzing the correlation between these variables with pulmonary tuberculosis. Study was done from July 2009 until September 2010, in Immanuel hospital Bandung and Stem Cell & Cancer Institute Jakarta. Compared with their healthy spouses the IFN-γ serum level in TB patients was not different statistically, the IFN-γ receptor expression in TB patients was higher (p=0,041), however, the IFN-γ receptor function of TB patients was lower (p=0,011). Correlation analysis showed that the only variable had correlation significantly with pulmonary tuberculosis was low function of IFN-γ receptor (p=0,026,OR 5,56). The expression of IFN-γ receptor in pulmonary tuberculosis patients was higher, while the function of IFN-γ receptor was lower than their healthy spouses. The low function of IFN-γ receptor had significantly correlation with pulmonary tuberculosis. Key Words: Tuberculosis, IFN-γ serum level, IFN-γ receptor expression and function.

Intraepithelial lymphocyte-derived interferon-γ evokes enterocyte apoptosis with parenteral nutrition in mice

2003 ◽  
Vol 284 (4) ◽  
pp. G629-G637 ◽  
Author(s):  
Hua Yang ◽  
Yongyi Fan ◽  
Daniel H. Teitelbaum
Keyword(s):  
Parenteral Nutrition ◽  
Fas Ligand ◽  
Interferon Γ ◽  
Intraepithelial Lymphocyte ◽  
Wild Type ◽  
Enterocyte Apoptosis ◽  
Resultant Increase ◽  
Ifn Γ ◽  
Fas L ◽  
Deficient Mice

Total parenteral nutrition (TPN) results in an increase in intraepithelial lymphocyte (IEL)-derived interferon-γ (IFN-γ) expression as well as an increase in epithelial cell (EC) apoptosis. This study examined the role that IEL-derived IFN-γ has in the increase in EC apoptosis. Mice received either TPN or oral feedings for 7 days. Small bowel EC apoptosis significantly rose in mice receiving TPN. The administration of TPN also significantly increased IEL-derived IFN-γ and Fas ligand (FasL) expression. EC apoptosis in IFN-γ knockout (IFNKO) mice that received TPN was significantly lower than in wild-type TPN mice. Sensitivity of EC to Fas-mediated apoptosis in IFNKO mice was significantly lower than in wild-type TPN mice. Apoptosis in Fas-deficient and FasL-deficient mice that received TPN was significantly lower than in wild-type mice that received TPN. The TPN-induced increase in IFN-γ expression appears to result in an increase in Fas-L expression and EC sensitivity to Fas, with a resultant increase in EC apoptosis. This may well be one of the mediators of increased EC apoptosis observed with TPN administration.

Lack of a Requirement for the Inhibitory Fcγ Receptor In IVIG-Mediated Treatment of ITP

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3338-3338
Author(s):  
Danila Leontyev ◽  
Yulia Katsman ◽  
Xue-Zhong Ma ◽  
Donald R. Branch
Keyword(s):  
Knockout Mice ◽  
Conflicts Of Interest ◽  
Inflammatory Diseases ◽  
Ivig Therapy ◽  
Ivig Treatment ◽  
Wild Type ◽  
Fcγ Receptor ◽  
Antiplatelet Antibody ◽  
And Function ◽  
Knockout Animals

Abstract Abstract 3338 One of the most quoted articles in publications and at International meetings regarding the mechanism of intravenous immunoglobulin (IVIg) therapy in autoimmune and inflammatory diseases is that by Samuelsson et al., Science 291, 484 (2001). This article deals with the mechanism of effect of IVIg being due to an increase in the expression and function of the inhibitory Fcγ receptor (FcγRIIB) in splenic macrophages. The conclusions in this Science paper are based primarily on the use of an experimental mouse model of immune thrombocytopenia (ITP) and mice made deficient in FcγRIIB (FcγRIIB-/- knockouts). We have not been able to support these previous findings but instead find the presence of FcγRIIB receptor not necessary for successful treatment of experimental ITP through IVIg treatment. Administration of IVIg to wild-type Balb/c mice previously made thrombocytopenic using an escalating dose of antiplatelet antibody, MWReg30, leads to amelioration of experimental ITP while in untreated mice, platelet counts stay close to nadir. Similar dynamics of the amelioration of ITP were found using splenectomized or FcγRIIB-/- knockout (Taconic Labs) Balb/c mice. However, as previously published (Blood 15, 558 (2003)), IVIg does not work with FcγRIIB-/- knockout mice that are on a mixed B6:129S4 background, obtained from the Jackson Labs. Indeed, B6 (129S4-Fcgr2btm1Rav/J) FcγRIIB-/- knockout mice made thrombocytopenic are completely unresponsive to IVIg treatment. However, surprisingly, when using the recommended control wild-type mice for this knockout, the B6.129SF2 mouse, we found that this wild-type FcγRIIB+/+ mouse also does not respond to IVIg treatment. Confirmation of genotype was done; thus, we suggest that something about the 129S background prevents a response to IVIg therapy and this phenomenon is independent of the FcγRIIB. We have confirmed that wild-type 129S4 mice made thrombocytopenic do not respond to IVIg. We have also examined the B6 FcγRIIB-/- knockout mice from Taconic Labs which are purported to be fully congenic and these mice also do not respond to IVIg. Because of the lack of response to IVIg of wild-type 129S4 mice, we believe that the Taconic B6 FcγRIIB-/- knockout mice may, in fact, be mixed background as are the Jackson mice. Thus, we plan to use SNP protocols for determination of congenicity, comparing C57BL/6 and 129S4 strains to Taconic and Jackson Labs B6 FcγRIIB-/- knockout mice. We expect to show that both B6 FcγRIIB-/- knockout animals are not fully congenic, being a mixture of both C57BL/6 and 129S4 strains. Previous publications that indicated a lack of response to IVIg using FcγRIIB-/- knockout mice either did not test the fully congenic Taconic Balb/c knockouts and/or failed to use the most suitable control animals with the nonfully congenic B6 knockouts, using instead, C57BL/6 wild-type mice which respond well to IVIg treatment. In order to avoid misinterpretation of results, all experiments testing the role for FcγRIIB in the mechanism of IVIg should be done using Taconic Balb/c FcγRIIB-/- knockout mice until congenicity can be established with the B6 knockout animals. These data taken together lead us to the conclusion that the presence of the FcγRIIB receptor is not important for the therapeutic action of IVIg. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Interferon γ Stabilizes the T Helper Cell Type 1 Phenotype

2001 ◽  
Vol 194 (2) ◽  
pp. 165-172 ◽  
Author(s):  
Yongkang Zhang ◽  
Ron Apilado ◽  
John Coleman ◽  
Shlomo Ben-Sasson ◽  
Sharon Tsang ◽  
...  
Keyword(s):  
Critical Role ◽  
Interferon Γ ◽  
T Helper Cell ◽  
Helper Cell ◽  
Wild Type ◽  
T Helper ◽  
Helper Cell Type ◽  
Ifn Γ ◽  
Th 1

T helper cell (Th)1-primed CD4 T cells from wild-type donors make little interleukin (IL)-4 when restimulated under Th2 conditions. However, such restimulation of Th1-primed cells from interferon (IFN)-γ2/− or IFN-γ receptor (IFN-γR)−/− mice resulted in substantial production of IL-4 and other Th2 cytokines. Adding IFN-γ to the priming culture markedly diminished the capacity of Th1-primed IFN-γ2/− cells to express IL-4. Even IFN-γ–producing cells from IFN-γR−/− mice could acquire IL-4–producing capacity. Thus, IFN-γ is not required for the development of IFN-γ–producing capacity, but it plays a critical role in suppressing the IL-4–producing potential of Th1 cells.

scholarly journals Role of Th22 Cells in the Pathogenesis of Autoimmune Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Qi Jiang ◽  
Guocan Yang ◽  
Fan Xiao ◽  
Jue Xie ◽  
Shengjun Wang ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Chemokine Receptors ◽  
Inflammatory Diseases ◽  
Biological Effects ◽  
Cell Subset ◽  
Interferon Γ ◽  
Th22 Cells ◽  
Tnf Α ◽  
Ifn Γ

Upon antigenic stimulation, naïve CD4+T cells differentiate into different subsets and secrete various cytokines to exert biological effects. Th22 cells, a newly identified CD4+T cell subset,are distinct from the Th1, Th2 and Th17 subsets. Th22 cells secrete certain cytokines such as IL-22, IL-13 and TNF-α, but not others, such as IL-17, IL-4, or interferon-γ (IFN-γ), and they express chemokine receptors CCR4, CCR6 and CCR10. Th22 cells were initially found to play a role in skin inflammatory diseases, but recent studies have demonstrated their involvement in the development of various autoimmune diseases. Here, we review research advances in the origin, characteristics and effector mechanisms of Th22 cells, with an emphasis on the role of Th22 cells and their main effector cytokine IL-22 in the pathogenesis of autoimmune diseases. The findings presented here may facilitate the development of new therapeutic strategies for targeting these diseases.

Histone Demethylase LSD1 Is Required to Repress Hematopoietic Stem Cell Signatures in Mature Blood Cells to Permit Terminal Differentiation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 550-550
Author(s):  
Marc A Kerenyi ◽  
Jessica Hsu ◽  
Zhen Shao ◽  
Stuart H Orkin
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Chromatin Immunoprecipitation ◽  
Expression Profiling ◽  
Myeloid Cells ◽  
Hematopoietic Differentiation ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Knock Out ◽  
Chromatin Immunoprecipitation Sequencing

Abstract Abstract 550 Lysine specific demethylase 1 (LSD1) is a demethylase that acts on mono- and dimethylated H3K4 (H3K4me1/2). Consistent with H3K4me2 (an active marker of transcription) as a substrate, LSD1 is part of a core complex with the co-repressor, CoREST and HDAC1/2. Previously our lab demonstrated that regulation of hematopoietic differentiation depends in part on the interaction of the growth factor independent transcription factors (= Gfi1 and Gfi1b) with the LSD1/CoREST/HDAC complex. We generated a conditional knock out mouse for LSD1 (LSD1fl/fl) to study its roles in hematopoiesis. Inducible deletion of LSD1fl/fl mice in all hematopoietic lineages with Mx-Cre resulted in severe neutropenia. Flow cytometric analysis showed that LSD1fl/fl Mx-Cre mice lacked Gr-1high Mac-1high double positive mature neutrophilic granulocytes in the bone marrow and the peripheral blood; however, the frequency of Gr-1dim Mac-1high (mainly consisting of promyelocytes and myeloblasts but not mature neutrophils) increased in frequency. To reveal the mechanism responsible for the observed neutropenia, we performed global mRNA expression profiling and chromatin immunoprecipitation sequencing (ChIPSeq) for H3K4 methylation states in Gr-1dim Mac-1high cells from LSD1fl/fl Mx-Cre and LSD1fl/fl mice. Five hundred ninety-eight genes (412 up / 186 down; p≤0.01, 2-fold cutoff) were differentially expressed in the absence of LSD1. Although we did not detect changes in expression of established myeloid transcription factors, including Pu.1, C/EBPα, C/EBPε or Gfi1, gene set enrichment analysis (GSEA) of Gr-1dim Mac-1high cells from LSD1fl/fl Mx-Cre using gene signatures for mature myeloid cells clearly showed that LSD1 deficient Gr-1dim Mac-1high cells failed to display a gene signature of differentiated myeloid cells (NES: 1.88; p≤0.003). Among the most highly upregulated genes, we observed genes highly expressed in hematopoietic stem and progenitor cells (HSPCs; i.e.: CD34 36.2-fold; HoxA9 26.3-fold; Sca-1 10.8-fold; Meis 1 2.6-fold). Therefore we performed GSEA using signatures from HSPCs (encompassing over 200 genes); the stem/progenitor gene set was highly significantly enriched (NES: −1.9; p<10−4) in LSD1 deficient Gr-1dim Mac-1high cells. Chromatin immunoprecipitation sequencing did not reveal any global changes in the amount of H3K4me2/3 histone methylation, however many genes critical for HSPCs, including Meis1 and the entire HoxA gene locus, where more strongly H3K4me2/3 marked than in control cells, which is in concord with the gene expression data. To determine if LSD1 represses stem/progenitor genes in additional lineages, we analyzed the effects of LSD1 loss in erythroid cell development through breeding with EpoR-Cre. Wild type, as well as control embryos, were recovered at Mendalian ratios up to E12.5, but no live LSD1fl/fl EpoR-Cre embryos were observed after E15.5. At E13.5, LSD1-deficient embryos were smaller and paler as compared to control embryos. Flow cytometry revealed a severe differentiation defect at the transition from pro-erythroblasts to basophilic erythroblasts, resulting in a paucity of more mature erythroid cells. To unravel molecular mechanisms responsible for this deficit, we performed gene expression profiling of wild type and knock out CD71+ c-kit+ Ter119lo pro-erythroblasts. Again, we did not detect changes in the expression levels of established erythroid transcription factors, including Gata-1, Klf1, SCL/Tal1, NF-E1, Ldb1, Lmo2 or Myb. By GSEA analysis we observed that LSD1 deficient CD71+ c-kit+ Ter119lo pro-erythroblasts displayed higher expression of the hematopoietic stem and progenitor cell gene signatures (NES: −2.4; p<10−4), a finding strikingly similar to the data in myeloid cells. Therefore, LSD1 is required in multiple hematopoietic lineages to repress stem/progenitor gene expression programs in maturing cells. We propose that repression of these early programs is essential for subsequent hematopoietic differentiation. Disclosures: No relevant conflicts of interest to declare.

Interferon-γ-Induced Upregulation of Immunoproteasome Subunit Assembly Overcomes Bortezomib Resistance of Leukemia Cell Lines Harbouring Bortezomib-Induced Mutations in Constitutive PSMB5

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1346-1346 ◽  
Author(s):  
Denise Niewerth ◽  
Niels Franke ◽  
Gerrit Jansen ◽  
Yehuda Assaraf ◽  
Johan van Meerloo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Acquired Resistance ◽  
Hematologic Malignancies ◽  
Interferon Γ ◽  
Resistant Cell ◽  
Proteasome Activity ◽  
Mrna Levels ◽  
Wild Type ◽  
Ic50 Values ◽  
Ifn Γ

Abstract Abstract 1346 Acquired resistance to the proteasome inhibitor (PI) bortezomib (BTZ) is an emerging factor limiting its efficacy in the treatment of hematologic malignancies. The clinical impact of acquired resistance has been shown in Multiple Myeloma (MM) patients who were re-treated with BTZ. Although BTZ-retreatment was found to be effective, the response rate as well as the duration of response were less as compared to initial treatment, indicating the development of BTZ-resistance in a subgroup of patients. In line with that, we previously found increased expression of constitutive proteasome (cP) subunit ß5 harbouring a mutation in the BTZ-binding pocket and a decreased expression of non-mutated immunoproteasome subunits in BTZ-resistant cell lines of hematologic malignancies (Franke and Niewerth et al, Leukemia 2012). We here explore whether upregulation of immunoproteasome (iP) expression could restore sensitivity in BTZ-resistant leukemia cells towards BTZ and two epxoyketone-based irreversible PIs; carfilzomib (CFZ) and the ß5i-targeted ONX 0914. BTZ-resistant cell lines were of multiple myeloma (8226), T-cell (CEM) and myelomonocytic (THP1) origin and displayed resistance towards cell growth inhibition in the presence of 7–200 nM BTZ. Induction of iP in wild type (WT) and BTZ-resistant 8226, CCRF-CEM and THP1 cells was achieved by exposure to 100U/ml Interferon- γ (IFN-γ) for 6–72 h. IFN-γ transiently increased (maximum between 24–48 hours) mRNA levels of β5i, β1i, and β2i up to 8-fold, 30-fold and 4-fold, respectively. These findings were corroborated at the β5i, β1i and β2i protein expression level using Western blot analysis. Following IFN-γ exposure, chymotrypsin-like proteasome activity increased up to 2.5-fold compared to unstimulated controls, trypsin-like activity increased up to 1.5-fold, whereas caspase-like activity was slightly decreased. Consistent with increased proteasome activity, there was also an increased expression of cell surface HLA Class I molecules. The impact of IFN-γ induced upregulation of iPs on the sensitivity to the PI BTZ, CFZ, and ONX 0914, defined by the decrease in IC50, is summarized in Table 1. 8226/BTZ100 cells became 4-fold more sensitive towards BTZ after IFN-γ exposure, whereas THP1/BTZ200 and CEM/BTZ200 cells displayed nearly 2-fold increased sensitivity. For CFZ, a modest level of sensitization was observed in all cell lines with high level BTZ resistance. Interestingly, for the immunoproteasome inhibitor ONX 0914, IC50 values were markedly decreased (7-fold for 8226/BTZ100 and 3-fold for THP1/BTZ200 and CEM/BTZ200 cells). Additionally, in 8226 cells with low levels of BTZ resistance (8226/BTZ7), IFN-γ restored parental cell sensitivity to ONX 0914. Restoration of PI sensitivity after IFN-γ exposure was further confirmed by activation of PARP cleavage and accumulation of ubiquitinated proteins, pointing to restoration of BTZ activity under proteasome inhibition and consequent induction of apoptosis. Finally, to provide evidence that upregulation of β5i and or β1i by IFN-γ was responsible for the observed sensitization, siRNA downregulation of β5i and β1i was applied prior to exposure to IFN-γ. Under these conditions, mRNA levels and proteasome activity of β5i remained suppressed, even after exposure to IFN-γ. Moreover, after β5i silencing, PI sensitization and apoptosis were attenuated. Silencing of β1i expression had no effect on PI-sensitization. In conclusion, down-regulation of β5i subunit expression is a major determinant of BTZ-resistance and increasing its proteasomal assembly after IFN-γ exposure facilitates restoration of sensitivity in BTZ-resistant leukemia cells towards cP inhibitors and in particular iP inhibitors. Table 1. IC50 values of PIs ± IFN-γ pre-incubation (48 hr) of wild type and BTZ-resistant hematologic cell lines Cell lines BTZ BTZ + IFNy SF ONX 0914 ONX 0914 + IFNy SF CFZ CFZ + IFNy SF 8226/wt 2.6 1.8 1.4 54 46 1.5 0.4 0.4 1 8226/BTZ7 13.5 5.8 2.3 99 47 2.1 0.9 0.8 1.1 8226/BTZ100 208 57 3.6 1837 249 7.4 28 13 2.2 CEM/wt 4.1 3.9 1.1 75 65 1.2 0.4 0.3 1.3 CEM/BTZ200 416 223 1.9 1763 566 3.1 42 26 1.6 THP1/wt 6.2 5.1 1.2 52 19 2.7 0.9 1.3 0.7 THP1/BTZ200 641 347 1.8 4236 1376 3.1 49 34 1.4 50% inhibitory concentration compared to untreated controls (IC50 nM) as determined in a 4 days growth inhibition assay (MTT). Results depicted are means of at least 3 separate experiments. SF: sensitization factor: IC50 control/IC50 with IFN-g. Disclosures: No relevant conflicts of interest to declare.

The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon γ production

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2899-2907 ◽  
Author(s):  
Duncan Howie ◽  
Susumo Okamoto ◽  
Svend Rietdijk ◽  
Kareem Clarke ◽  
Ninghai Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Dna Synthesis ◽  
Interferon Γ ◽  
T Cell Proliferation ◽  
Wild Type ◽  
Ifn Γ

CD150 (signaling lymphocyte activation molecule [SLAM]) is a self-ligand cell surface glycoprotein expressed on T cells, B cells, macrophages, and dendritic cells. To further explore the role of CD150 signaling in costimulation and TH1 priming we have generated a panel of rat antimouse CD150 monoclonal antibodies. CD150 cell surface expression is up-regulated with rapid kinetics in activated T cells and lipopolysaccharide/interferon γ (IFN-γ)–activated macrophages. Anti-CD150 triggering induces strong costimulation of T cells triggered through CD3. DNA synthesis of murine T cells induced by anti-CD150 is not dependent on SLAM-associated protein (SAP, SH2D1A), because anti-CD150 induces similar levels of DNA synthesis in SAP−/− T cells. Antibodies to CD150 also enhance IFN-γ production both in wild-type and SAP−/− T cells during primary stimulation. The level of IFN-γ production is higher in SAP−/− T cells than in wild-type T cells. Anti-CD150 antibodies also synergize with interleukin 12 (IL-12) treatment in up-regulation of IL-12 receptor β2 mRNA during TH1 priming, and inhibit primary TH2 polarization in an IFN-γ–dependent fashion. Cross-linking CD150 on CD4 T cells induces rapid serine phosphorylation of Akt/PKB. We speculate that this is an important pathway contributing to CD150-mediated T-cell proliferation.

scholarly journals Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines

2012 ◽  
Vol 302 (2) ◽  
pp. C392-C404 ◽  
Author(s):  
Jamie C. Zampell ◽  
Tomer Avraham ◽  
Nicole Yoder ◽  
Nicholas Fort ◽  
Alan Yan ◽  
...  
Keyword(s):  
T Cell ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Expression Patterns ◽  
Interferon Γ ◽  
Wild Type ◽  
Lymphatic Function ◽  
Ifn Γ ◽  
Factor C ◽  
Lymphatic Fluid

Lymphangiogenic cytokines such as vascular endothelial growth factor-C (VEGF-C) are critically required for lymphatic regeneration; however, in some circumstances, lymphatic function is impaired despite normal or elevated levels of these cytokines. The recent identification of anti-lymphangiogenic molecules such as interferon-γ (IFN-γ), transforming growth factor-β1, and endostatin has led us to hypothesize that impaired lymphatic function may represent a dysregulated balance in the expression of pro/anti-lymphangiogenic stimuli. We observed that nude mice have significantly improved lymphatic function compared with wild-type mice in a tail model of lymphedema. We show that gradients of lymphatic fluid stasis regulate the expression of lymphangiogenic cytokines (VEGF-A, VEGF-C, and hepatocyte growth factor) and that paradoxically the expression of these molecules is increased in wild-type mice. More importantly, we show that as a consequence of T-cell-mediated inflammation, these same gradients also regulate expression patterns of anti-lymphangiogenic molecules corresponding temporally and spatially with impaired lymphatic function in wild-type mice. We show that neutralization of IFN-γ significantly increases inflammatory lymph node lymphangiogenesis independently of changes in VEGF-A or VEGF-C expression, suggesting that alterations in the balance of pro- and anti-lymphangiogenic cytokine expression can regulate lymphatic vessel formation. In conclusion, we show that gradients of lymphatic fluid stasis regulate not only the expression of pro-lymphangiogenic cytokines but also potent suppressors of lymphangiogenesis as a consequence of T-cell inflammation and that modulation of the balance between these stimuli can regulate lymphatic function.

Interferon-γ: a key contributor to hyperoxia-induced lung injury in mice

2004 ◽  
Vol 287 (5) ◽  
pp. L1042-L1047 ◽  
Author(s):  
Mitsuhiro Yamada ◽  
Hiroshi Kubo ◽  
Seiichi Kobayashi ◽  
Kota Ishizawa ◽  
Hidetada Sasaki
Keyword(s):  
Lung Injury ◽  
Cell Activation ◽  
Late Phase ◽  
Neutrophil Migration ◽  
Lavage Fluid ◽  
Interferon Γ ◽  
Wild Type ◽  
Permeability Changes ◽  
Significant Difference ◽  
Ifn Γ

Hyperoxia-induced lung injury complicates the care of many critically ill patients who receive supplemental oxygen therapy. Hyperoxic injury to lung tissues is mediated by reactive oxygen species, inflammatory cell activation, and release of cytotoxic cytokines. IFN-γ is known to be induced in lungs exposed to high concentrations of oxygen; however, its contribution to hyperoxia-induced lung injury remains unclear. To determine whether IFN-γ contributes to hyperoxia-induced lung injury, we first used anti-mouse IFN-γ antibody to blockade IFN-γ activity. Administration of anti-mouse IFN-γ antibody inhibited hyperoxia-induced increases in pulmonary alveolar permeability and neutrophil migration into lung air spaces. To confirm that IFN-γ contributes to hyperoxic lung injury, we then simultaneously exposed IFN-γ-deficient (IFN-γ−/−) mice and wild-type mice to hyperoxia. In the early phase of hyperoxia, permeability changes and neutrophil migration were significantly reduced in IFN-γ−/− mice compared with wild-type mice, although the differences in permeability changes and neutrophil migration between IFN-γ−/− mice and wild-type mice were not significant in the late phase of hyperoxia. The concentrations of IL-12 and IL-18, two cytokines that play a role in IFN-γ induction, significantly increased in bronchoalveolar lavage fluid after exposure to hyperoxia in both IFN-γ−/− mice and wild-type mice, suggesting that hyperoxia initiates upstream events that result in IFN-γ production. Although there was no significant difference in overall survival, IFN-γ−/− mice had a better early survival rate than did the wild-type mice. Therefore, these data strongly suggest that IFN-γ is a key molecular contributor to hyperoxia-induced lung injury.

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