scholarly journals Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10

Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3877-3882 ◽  
Author(s):  
C Sgadari ◽  
AL Angiolillo ◽  
G Tosato
Keyword(s):  
Interleukin 12 ◽  
Human Interferon ◽  
Ifn Gamma ◽  
Mouse Splenocytes ◽  
Angiogenesis Inhibition ◽  
Inhibition Of Angiogenesis ◽  
Inducible Protein ◽  
Interferon Inducible Protein

Interleukin 12 (IL-12), a multifunctional cytokine produced by macrophages and B-cell lines, induces interferon-gamma (IFN-gamma) production, stimulates growth of both T and natural killer cells, promotes Th1-type helper T-cell responses, and inhibits neovascularization. Because the human interferon-inducible protein 10 (IP-10) can also inhibit neovascularization, we tested whether IP-10, induced by IL-12 through the intermediate IFN-gamma, might be a mediator of IL-12 angiogenesis inhibition. We report here that murine IL-12 profoundly inhibited basic fibroblast growth factor (bFGF)- induced Matrigel neovascularization in vivo, and that this effect of IL- 12 was neutralized by systemic administration of antibodies to either murine IFN-gamma or IP-10. Murine IL-12 induced murine IP-10 expression in mouse splenocytes, and human IFN-gamma induced human IP-10 expression in purified human endothelial cells, suggesting that IL-12 can induce IP-10 expression in certain cells. These results document the important role of IP-10 as a mediator of angiogenesis inhibition by IL-12, and raise the possibility that IP-10 may also contribute to the antitumor effect of IL-12.

scholarly journals Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo.

1995 ◽  
Vol 182 (1) ◽  
pp. 155-162 ◽  
Author(s):  
A L Angiolillo ◽  
C Sgadari ◽  
D D Taub ◽  
F Liao ◽  
J M Farber ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Potent Inhibitor ◽  
Human Interferon ◽  
Endothelial Cell Differentiation ◽  
Dose Dependent Fashion ◽  
Inducible Protein ◽  
And Migration ◽  
Interferon Inducible Protein

Human interferon-inducible protein 10 (IP-10), a member of the alpha chemokine family, inhibits bone marrow colony formation, has antitumor activity in vivo, is chemoattractant for human monocytes and T cells, and promotes T cell adhesion to endothelial cells. Here we report that IP-10 is a potent inhibitor of angiogenesis in vivo. IP-10 profoundly inhibited basic fibroblast growth factor-induced neovascularization of Matrigel (prepared by H. K. Kleinman) injected subcutaneously into athymic mice. In addition, IP-10, in a dose-dependent fashion, suppressed endothelial cell differentiation into tubular capillary structures in vitro. IP-10 had no effect on endothelial cell growth, attachment, and migration as assayed in vitro. These results document an important biological property of IP-10 and raise the possibility that IP-10 may participate in the regulation of angiogenesis during inflammation and tumorigenesis.

scholarly journals Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

1994 ◽  
Vol 179 (4) ◽  
pp. 1273-1283 ◽  
Author(s):  
R Manetti ◽  
F Gerosa ◽  
M G Giudizi ◽  
R Biagiotti ◽  
P Parronchi ◽  
...  
Keyword(s):  
T Cells ◽  
Interferon Gamma ◽  
Specific Antigen ◽  
Th2 Cells ◽  
Interleukin 12 ◽  
T Helper ◽  
Ifn Gamma ◽  
Selection Of

Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

scholarly journals Resistance to Acute Babesiosis Is Associated with Interleukin-12- and Gamma Interferon-Mediated Responses and Requires Macrophages and Natural Killer Cells

2003 ◽  
Vol 71 (4) ◽  
pp. 2002-2008 ◽  
Author(s):  
Irma Aguilar-Delfin ◽  
Peter J. Wettstein ◽  
David H. Persing
Keyword(s):  
Nk Cells ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
No Production ◽  
Cytokine Responses ◽  
Early Production ◽  
Ifn Γ ◽  
Crucial Part

ABSTRACT We examined the role of the cytokines gamma interferon (IFN-γ) and interleukin-12 (IL-12) in the model of acute babesiosis with the WA1 Babesia. Mice genetically deficient in IFN-γ-mediated responses (IFNGR2KO mice) and IL-12-mediated responses (Stat4KO mice) were infected with the WA1 Babesia, and observations were made on the course of infection and cytokine responses. Levels of IFN-γ and IL-12 in serum increased 24 h after parasite inoculation. The augmented susceptibility observed in IFNGR2KO and Stat-4KO mice suggests that the early IL-12- and IFN-γ-mediated responses are involved in protection against acute babesiosis. Resistance appears to correlate with an increase in nitric oxide (NO) production. In order to assess the contribution of different cell subsets to resistance against the parasite, we also studied mice lacking B cells, CD4+ T cells, NK cells, and macrophages. Mice genetically deficient in B lymphocytes or CD4+ T lymphocytes were able to mount protective responses comparable to those of immunosufficient mice. In contrast, in vivo depletion of macrophages or NK cells resulted in elevated susceptibility to the infection. Our observations suggest that a crucial part of the response that protects from the pathogenic Babesia WA1 is mediated by macrophages and NK cells, probably through early production of IL-12 and IFN-γ, and induction of macrophage-derived effector molecules like NO.

Abstract 644: Role of Micro RNA LET-7F in Cigarette Smoke-Induced Impairment of Neovascularization

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Wahiba Dhahri ◽  
Sylvie Dussault ◽  
Paola Haddad ◽  
Julie Turgeon ◽  
Sophie Tremblay ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Vascular Endothelial Cells ◽  
Capillary Density ◽  
Tube Formation ◽  
Micro Rna ◽  
Cellular Migration ◽  
Mirna Array ◽  
Inhibition Of Angiogenesis

Background: Exposure to cigarette smoke is associated with impaired neovascularization in response to ischemia. The precise mechanisms involved in that process remain to be determined. Micro RNA (miR) are emerging as key regulators of several physiological processes, including angiogenesis. Here we investigated the potential role of miRs for the modulation of neovascularization in the context of cigarette smoking. Methods and Results: Human Umbilical Vascular Endothelial Cells (HUVECs) were exposed or not to cigarette smoke extracts (CSE). Using Affimetrix GeneChip miRNA array analysis, we found that the pro-angiogenic miR let-7f was downregulated by 40% in HUVECs exposed to CSE. Using an inhibitor of let-7f, we demonstrated reduced migration and tube formation in HUVECs, reproducing the phenotype induced by CSE. A let-7f mimic could rescue cellular migration and tube formation in HUVECs exposed to CSE. Moreover, the expression of let-7f is significantly reduced in the ischemic muscles of mice exposed to cigarette smoke (CS). In vivo, hindlimb ischemia was surgically provoked by femoral artery removal to mice exposed (SMK) or not to CS for two weeks with a local injection of a control or a let-7f mimic. Let-7f mimic could rescue blood flow recuperation and capillary density in ischemic muscles 21 days post-ischemia associated with improved mobility. We found that CS was associated with reduced number of endothelial progenitor cells (EPCs) and impairment of angiogenic activities. Importantly, let-7f mimic rescued EPC number and EPC functional activities in SMK group. TGF-β-RI and HIF1AN are predicted to be targeted by let-7f and both are increased in SMK mice, whereas the expression of HIF-1a and VEGF are reduced in these mice. Interestingly, SMK mice injected with a let-7f mimic have decreased muscle expression of TGF-β-RI and HIF1AN associated with normalized HIF-1 and VEGF expression. Conclusion: Our results suggest that a reduction in the expression of let-7f could be involved in the cigarette smoke-induced inhibition of angiogenesis through modulation of TGF-β-RI and HIF1AN. Overexpression of let-7f using a miR mimic could constitute a novel therapeutic strategy to improve ischemia-induced neovascularization in pathological conditions.

RU-486 blocks differentially suppressive effect of stress on in vivo anti-KLH immunoglobulin response

1996 ◽  
Vol 271 (5) ◽  
pp. R1344-R1352 ◽  
Author(s):  
M. Fleshner ◽  
F. X. Brennan ◽  
K. Nguyen ◽  
L. R. Watkins ◽  
S. F. Maier
Keyword(s):  
B Cells ◽  
Keyhole Limpet Hemocyanin ◽  
Suppressive Effect ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Th1 Cell ◽  
Ifn Gamma ◽  
Ru 486

Exposure to stressors can affect various aspects of immune function, including the antibody response. We have previously reported that rats exposed to an acute session of inescapable tail shock (IS) show long-term reductions in anti-keyhole limpet hemocyanin (KLH) immunoglobulin (Ig) M and IgG and a failure to expand Th1-like cells in response to KLH. To further investigate the potential role of decreased Th1-like cells in the IS-induced reduction of anti-KLH Ig, we examined two isotypes of IgG, IgG1 and IgG2a. Isotype switching is under cytokine control. Interleukin-4 helps B cells switch from making IgM to making IgG1, whereas interferon (IFN)-gamma helps B cells switch from making IgM to making IgG2a. In this paper we report that IS exposure reduces IFN-gamma levels 4 days after exposure to IS+KLH compared with immunized home cage controls. In addition, IS exposure reduced the Th1 cytokine-sensitive anti-KLH IgG2a but not Th2 cytokine-sensitive anti-KLH IgG1. This pattern of isotype reduction suggests that a failure to expand the Th1 cell, which results in less IFN-gamma, may contribute to the the IS-induced reduction in anti-KLH Ig. Glucocorticoids (GCs) differentially regulate Th1 and Th2 cells. Administration of the type II GC receptor antagonist RU-486 before IS blocked the IS-induced suppression in anti-KLH IgM, IgG, and IgG2a. Corticosterone (2.5 mg/kg), however, did not produce the suppression in anti-KLH Ig. These results support a role of corticosterone in mediating IS-induced reductions in in vivo antibody.

scholarly journals Role of beta1 and beta2 subunits of the interleukin-12 receptor in determining T helper 1/T helper 2 responses in vivo in the rat

Immunology ◽  
2000 ◽  
Vol 99 (1) ◽  
pp. 109-112 ◽  
Author(s):  
K. M. Gillespie ◽  
C.-C. Szeto ◽  
V. M. Betin ◽  
P. W. Mathieson
Keyword(s):  
Interleukin 12 ◽  
T Helper ◽  
T Helper 1 ◽  
T Helper 2

scholarly journals Human interferon-inducible protein-10 induces mononuclear cell infiltration in mice and promotes the migration of human T lymphocytes into the peripheral tissues and human peripheral blood lymphocytes-SCID mice

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1423-1431 ◽  
Author(s):  
DD Taub ◽  
DL Longo ◽  
WJ Murphy
Keyword(s):  
T Cell ◽  
Mononuclear Cell ◽  
Human Peripheral Blood ◽  
Peripheral Blood Lymphocytes ◽  
Cell Infiltration ◽  
Mononuclear Cell Infiltration ◽  
Human T Cell ◽  
Inducible Protein ◽  
Interferon Inducible Protein

The human cytokine, interferon-inducible protein-10 (IP-10), is a small glycoprotein secreted by activated monocytes, T cells, keratinocytes, astrocytes, and endothelial cells and is structurally related to the alpha subfamily of chemotactic cytokines called chemokines (Taub and Oppenheim, Cytokine 5:175, 1993). However, in contrast to other alpha chemokines that induce neutrophil migration, IP-10 has been shown to chemoattract monocytes and T lymphocytes in vitro, suggesting a role in T-cell-mediated immune responses. We therefore examined the effects of human IP-10 after in vivo administration. IP-10 induces significant mononuclear cell infiltration after subcutaneous injections in normal mice. In an effort to study the in vivo effects of IP-10 on human leukocyte migration, we then examined the ability of recombinant human IP-10 (rhIP-10) to induce human-T-cell infiltration using a human/severe combined immune deficiency (SCID) mouse model. SCID mice received an intraperitoneal injection of human peripheral blood lymphocytes (10(8) cells), followed by a subcutaneous injection of rhIP- 10 (1 micrograms/injection) in the hind flank for 4 hours or sequential injections for 3 days. The skin and underlying tissue from the rhIP-10 injection site were then biopsied and examined for the extent of mononuclear cell infiltration. rhIP-10 again induced significant mononuclear cell accumulation 72 hours after injection. Immunohistologic evaluation determined that a significant number of human CD3+ T cells were recruited in response to rhIP-10 injections. These results show that rhIP-10 is capable of inducing human T-cell migration in vivo and may play an important role in monocyte and lymphocyte recruitment into inflammatory sites.

scholarly journals Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients

2005 ◽  
Vol 201 (9) ◽  
pp. 1503-1517 ◽  
Author(s):  
David H. Chang ◽  
Keren Osman ◽  
John Connolly ◽  
Anjli Kukreja ◽  
Joseph Krasovsky ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Advanced Cancer ◽  
Serum Levels ◽  
Nkt Cells ◽  
Interleukin 12 ◽  
Cell Immunity ◽  
Galactosyl Ceramide ◽  
Inducible Protein

Natural killer T (NKT) cells are distinct glycolipid reactive innate lymphocytes that are implicated in the resistance to pathogens and tumors. Earlier attempts to mobilize NKT cells, specifically, in vivo in humans met with limited success. Here, we evaluated intravenous injection of monocyte-derived mature DCs that were loaded with a synthetic NKT cell ligand, α-galactosyl-ceramide (α-GalCer; KRN-7000) in five patients who had advanced cancer. Injection of α-GalCer–pulsed, but not unpulsed, dendritic cells (DCs) led to >100-fold expansion of several subsets of NKT cells in all patients; these could be detected for up to 6 mo after vaccination. NKT activation was associated with an increase in serum levels of interleukin-12 p40 and IFN-γ inducible protein-10. In addition, there was an increase in memory CD8+ T cells specific for cytomegalovirus in vivo in response to α-GalCer–loaded DCs, but not unpulsed DCs. These data demonstrate the feasibility of sustained expansion of NKT cells in vivo in humans, including patients who have advanced cancer, and suggest that NKT activation might help to boost adaptive T cell immunity in vivo.

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