Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3554-3561 ◽  
Author(s):  
Paul Proost ◽  
Evemie Schutyser ◽  
Patricia Menten ◽  
Sofie Struyf ◽  
Anja Wuyts ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Active Form ◽  
Feedback Regulation ◽  
Negative Feedback Regulation ◽  
Amino Terminal ◽  
Dpp Iv ◽  
Immunodeficiency Virus ◽  
Membrane Bound ◽  
Ifn Γ ◽  
Inducible Protein

Abstract The interferon (IFN)–inducible chemokines, specifically, IFN-γ–inducible protein-10 (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T-cell α-chemoattractant (I-TAC), share a unique CXC chemokine receptor (CXCR3). Recently, the highly specific membrane-bound protease and lymphocyte surface marker CD26/dipeptidyl peptidase IV (DPP IV) was found to be responsible for posttranslational processing of chemokines. Removal of NH2-terminal dipeptides by CD26/DPP IV alters chemokine receptor binding and signaling, and hence inflammatory and anti–human immunodeficiency virus (HIV) activities. CD26/DPP IV and CXCR3 are both markers for Th1 lymphocytes and, moreover, CD26/DPP IV is present in a soluble, active form in human plasma. This study reports that at physiologic enzyme concentrations CD26/DPP IV cleaved 50% of I-TAC within 2 minutes, whereas for IP-10 and Mig the kinetics were 3- and 10-fold slower, respectively. Processing of IP-10 and I-TAC by CD26/DPP IV resulted in reduced CXCR3-binding properties, loss of calcium-signaling capacity through CXCR3, and more than 10-fold reduced chemotactic potency. Moreover, IP-10 and I-TAC cleaved by CD26/DPP IV acted as chemotaxis antagonists and CD26/DPP IV–truncated IP-10 and Mig retained their ability to inhibit the angiogenic activity of interleukin-8 in the rabbit cornea micropocket model. These data demonstrate a negative feedback regulation by CD26/DPP IV in CXCR3-mediated chemotaxis without affecting the angiostatic potential of the CXCR3 ligands IP-10 and Mig.

scholarly journals SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Mohamed Luban Sobah ◽  
Clifford Liongue ◽  
Alister C. Ward
Keyword(s):  
Immune Cell ◽  
Inflammatory Diseases ◽  
Feedback Regulation ◽  
Cytokine Signaling ◽  
Negative Feedback Regulation ◽  
Autoimmune Conditions ◽  
Socs Proteins ◽  
Ifn Γ ◽  
And Function ◽  
Immune Defects

Cytokine signaling represents one of the cornerstones of the immune system, mediating the complex responses required to facilitate appropriate immune cell development and function that supports robust immunity. It is crucial that these signals be tightly regulated, with dysregulation underpinning immune defects, including excessive inflammation, as well as contributing to various immune-related malignancies. A specialized family of proteins called suppressors of cytokine signaling (SOCS) participate in negative feedback regulation of cytokine signaling, ensuring it is appropriately restrained. The eight SOCS proteins identified regulate cytokine and other signaling pathways in unique ways. SOCS1–3 and CISH are most closely involved in the regulation of immune-related signaling, influencing processes such polarization of lymphocytes and the activation of myeloid cells by controlling signaling downstream of essential cytokines such as IL-4, IL-6, and IFN-γ. SOCS protein perturbation disrupts these processes resulting in the development of inflammatory and autoimmune conditions as well as malignancies. As a consequence, SOCS proteins are garnering increased interest as a unique avenue to treat these disorders.

scholarly journals Shared Usage of the Chemokine Receptor CXCR4 by Primary and Laboratory-Adapted Strains of Feline Immunodeficiency Virus

1999 ◽  
Vol 73 (5) ◽  
pp. 3661-3671 ◽  
Author(s):  
Jennifer Richardson ◽  
Gianfranco Pancino ◽  
Rastine Merat ◽  
Thierry Leste-Lasserre ◽  
Anne Moraillon ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Feline Immunodeficiency Virus ◽  
Type I ◽  
Dependent Manner ◽  
Amino Terminal ◽  
Species Origin ◽  
Chemokine Receptor Cxcr4 ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Strains of the feline immunodeficiency virus (FIV) presently under investigation exhibit distinct patterns of in vitro tropism. In particular, the adaptation of FIV for propagation in Crandell feline kidney (CrFK) cells results in the selection of strains capable of forming syncytia with cell lines of diverse species origin. The infection of CrFK cells by CrFK-adapted strains appears to require the chemokine receptor CXCR4 and is inhibited by its natural ligand, stromal cell-derived factor 1α (SDF-1α). Here we found that inhibitors of CXCR4-mediated infection by human immunodeficiency virus type I (HIV-1), such as the bicyclam AMD3100 and short peptides derived from the amino-terminal region of SDF-1α, also blocked infection of CrFK by FIV. Nevertheless, we observed differences in the ranking order of the peptides as inhibitors of FIV and HIV-1 and showed that such differences are related to the species origin of CXCR4 and not that of the viral envelope. These results suggest that, although the envelope glycoproteins of FIV and HIV-1 are substantially divergent, FIV and HIV-1 interact with CXCR4 in a highly similar manner. We have also addressed the role of CXCR4 in the life cycle of primary isolates of FIV. Various CXCR4 ligands inhibited infection of feline peripheral blood mononuclear cells (PBMC) by primary FIV isolates in a concentration-dependent manner. These ligands also blocked the viral transduction of feline PBMC by pseudotyped viral particles when infection was mediated by the envelope glycoprotein of a primary FIV isolate but not by the G protein of vesicular stomatitis virus, indicating that they act at an envelope-mediated step and presumably at viral entry. These findings strongly suggest that primary and CrFK-adapted strains of FIV, despite disparate in vitro tropisms, share usage of CXCR4.

scholarly journals Cross-Reactive Cytotoxic T Lymphocytes against Human Immunodeficiency Virus Type 1 Protease and Gamma Interferon-Inducible Protein 30

2005 ◽  
Vol 79 (9) ◽  
pp. 5529-5536 ◽  
Author(s):  
R. D. Mason ◽  
M. I. Bowmer ◽  
C. M. Howley ◽  
M. D. Grant
Keyword(s):  
Cytotoxic T Lymphocytes ◽  
Signal Peptide ◽  
Effector Cells ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Inducible Protein ◽  
Hiv 1 ◽  
Stimulation Of

ABSTRACT The gamma interferon (IFN-γ)-inducible protein 30 (IP-30) signal peptide −11 to −3 (LLDVPTAAV) is a prominent self peptide expressed with the class I human histocompatibility leukocyte antigen A2 (HLA-A2). Stimulation of peripheral blood mononuclear cells (PBMC) from HLA-A2 human immunodeficiency virus type 1 (HIV-1)-infected individuals with an HLA-A2-restricted HIV protease (PR) peptide 76-84 (LVGPTPVNI) activated cytotoxic T lymphocytes (CTL) against the IP-30 signal peptide. Since HIV-1 PR 76-84 stimulated CD8+ T cells from these individuals to secrete IFN-γ, we tested whether the activation of IP-30-specific CTL in vitro resulted from T-cell cross-reactivity or from up-regulation of IP-30 by IFN-γ. Neither high levels of exogenous IFN-γ nor incubation of PBMC with other HIV peptides triggering substantial IFN-γ release activated IP-30-specific CTL. Although the IP-30 signal peptide did not stimulate IFN-γ release from freshly isolated PBMC, it activated CTL in vitro against itself and HIV PR 76-84. Peptide-stimulated IFN-γ release, cold target inhibition, and HLA-A2/immunoglobulin dimer-mediated binding and depletion of effector cells all indicated that in vitro stimulation with HIV PR 76-84 or the IP-30 signal peptide activated a comparable population of cross-reactive effector cells. Neither IP-30 nor HIV PR 76-84 activated CTL against themselves following in vitro stimulation of PBMC from non-HIV-infected HLA-A2 individuals. Peptide titrations indicated higher-avidity T-cell interactions with HIV PR 76-84 than with the IP-30 signal peptide. These data indicate that HIV PR 76-84 is a heteroclitic variant of the IP-30 signal peptide −11 to −3, which has implications for immune memory and autoimmunity.

scholarly journals Negative Feedback Regulation of Met-Dependent Invasive Growth by Notch

2005 ◽  
Vol 25 (10) ◽  
pp. 3982-3996 ◽  
Author(s):  
M. Cristina Stella ◽  
Livio Trusolino ◽  
Selma Pennacchietti ◽  
Paolo M. Comoglio
Keyword(s):  
Negative Feedback ◽  
Regulatory Gene ◽  
Active Form ◽  
Feedback Regulation ◽  
Branching Morphogenesis ◽  
Ras Signaling ◽  
Invasive Growth ◽  
Negative Feedback Regulation ◽  
Tracheal System ◽  
Transcriptional Induction

ABSTRACT The hepatocyte growth factor (HGF) receptor encoded by the Met oncogene controls a genetic program—known as “invasive growth”—responsible for several developmental processes and involved in cancer invasion and metastasis. This program functions through several regulatory gene products, as yet largely unknown, both upstream and downstream of Met. Here we show that activation of the Notch receptor results in transcriptional down-regulation of Met, suppression of HGF-dependent Ras signaling, and impairment of HGF-dependent cellular responses. In turn, Met activation leads to transcriptional induction of the Notch ligand Delta and the Notch effector HES-1, indicating that Met is able to self-tune its own protein levels and the ensuing biochemical and biological outputs through stimulation of the Notch pathway. By using branching morphogenesis of the tracheal system in Drosophila as a readout of invasive growth, we also show that exogenous expression of a constitutively active form of human Met induces enhanced sprouting of the tracheal tree, a phenotype that is further increased in embryos lacking Notch function. These results unravel an in-built mechanism of negative feedback regulation in which Met activation leads to transcriptional induction of Notch function, which in turn limits HGF activity through repression of the Met oncogene.

scholarly journals Negative Feedback Regulation of IFN-γ Pathway by IFN Regulatory Factor 2 in Esophageal Cancers

2008 ◽  
Vol 68 (4) ◽  
pp. 1136-1143 ◽  
Author(s):  
Yan Wang ◽  
Dongping Liu ◽  
Pingping Chen ◽  
H. Phillip Koeffler ◽  
Xiangjun Tong ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Feedback Regulation ◽  
Regulatory Factor ◽  
Negative Feedback Regulation ◽  
Esophageal Cancers ◽  
Ifn Γ

scholarly journals Immunogenicity of HIV-1-Based Virus-Like Particles with Increased Incorporation and Stability of Membrane-Bound Env

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 239
Author(s):  
Christopher A. Gonelli ◽  
Hannah A. D. King ◽  
Charlene Mackenzie ◽  
Secondo Sonza ◽  
Rob J. Center ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Neutralization Activity ◽  
Virus Like Particles ◽  
Antibody Isotypes ◽  
Immunodeficiency Virus ◽  
Proline Substitution ◽  
Membrane Bound ◽  
Antibody Epitopes ◽  
Hiv 1

An optimal prophylactic vaccine to prevent human immunodeficiency virus (HIV-1) transmission should elicit protective antibody responses against the HIV-1 envelope glycoprotein (Env). Replication-incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present virion-associated Env with a native-like structure during vaccination that closely resembles that encountered on infectious virus. Here, we optimized the incorporation of Env into previously designed mature-form VLPs (mVLPs) and assessed their immunogenicity in mice. The incorporation of Env into mVLPs was increased by replacing the Env transmembrane and cytoplasmic tail domains with those of influenza haemagglutinin (HA-TMCT). Furthermore, Env was stabilized on the VLP surface by introducing an interchain disulfide and proline substitution (SOSIP) mutations typically employed to stabilize soluble Env trimers. The resulting mVLPs efficiently presented neutralizing antibody epitopes while minimizing exposure of non-neutralizing antibody sites. Vaccination of mice with mVLPs elicited a broader range of Env-specific antibody isotypes than Env presented on immature VLPs or extracellular vesicles. The mVLPs bearing HA-TMCT-modified Env consistently induced anti-Env antibody responses that mediated modest neutralization activity. These mVLPs are potentially useful immunogens for eliciting neutralizing antibody responses that target native Env epitopes on infectious HIV-1 virions.

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