scholarly journals Inactivation of Interleukin‐4 Receptor α Signaling in Myeloid Cells Protects Mice From Angiotensin II/High Salt–Induced Cardiovascular Dysfunction Through Suppression of Fibrotic Remodeling

2021 ◽  
Author(s):  
Jianrui Song ◽  
Ryan A. Frieler ◽  
Thomas M. Vigil ◽  
Jun Ma ◽  
Frank Brombacher ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Macrophage Activation ◽  
Substantial Reduction ◽  
High Salt ◽  
Interleukin 4 ◽  
Low Grade ◽  
Cardiovascular Remodeling ◽  
Arginase 1 ◽  
Interleukin 4 Receptor

Background Hypertension‐induced cardiovascular remodeling is characterized by chronic low‐grade inflammation. Interleukin‐4 receptor α (IL‐4Rα) signaling is importantly involved in cardiovascular remodeling, however, the target cell type(s) is unclear. Here, we investigated the role of myeloid‐specific IL‐4Rα signaling in cardiovascular remodeling induced by angiotensin II and high salt. Methods and Results Myeloid IL‐4Rα deficiency suppressed both the in vitro and in vivo expression of alternatively activated macrophage markers including Arg1 (arginase 1), Ym1 (chitinase 3‐like 3), and Relmα/Fizz1 (resistin‐like molecule α). After angiotensin II and high salt treatment, myeloid‐specific IL‐4Rα deficiency did not change hypertrophic remodeling within the heart and aorta. However, myeloid IL‐4Rα deficiency resulted in a substantial reduction in fibrosis through the suppression of profibrotic pathways and the enhancement of antifibrotic signaling. Decreased fibrosis was associated with significant preservation of myocardial function in MyIL4RαKO mice and was mediated by attenuated alternative macrophage activation. Conclusions Myeloid IL‐4Rα signaling is substantially involved in fibrotic cardiovascular remodeling by controlling alternative macrophage activation and regulating fibrosis‐related signaling. Inhibiting myeloid IL‐4Rα signaling may be a potential strategy to prevent hypertensive cardiovascular diseases.

scholarly journals Characterization and pharmacokinetic parameters of recombinant soluble interleukin-4 receptor

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2396-2403 ◽  
Author(s):  
CA Jacobs ◽  
DH Lynch ◽  
ER Roux ◽  
R Miller ◽  
B Davis ◽  
...  
Keyword(s):  
Half Life ◽  
Integral Membrane Protein ◽  
Interleukin 4 ◽  
Soluble Form ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Cdna Clones ◽  
Elimination Half ◽  
Interleukin 4 Receptor

Abstract The interleukin-4 receptor (IL-4R) is expressed as a 140-Kd membrane glycoprotein that binds IL-4 with high affinity. Recently, cDNA clones for the murine IL-4R have been isolated. One clone encodes an integral membrane protein, while another encodes a protein in which translation is terminated before the transmembrane region, thus producing a soluble form of the IL-4R (sIL-4R). HeLa cell clones overexpressing sIL-4R were isolated using a novel filter-overlay and 125I-IL-4 ligand binding technique. Quantitative analysis demonstrated that the kinetics and affinity of IL-4 binding to the recombinant sIL-4R were similar to the native membrane-bound IL-4R. As low doses of sIL-4R specifically inhibited IL-4-induced proliferative responses in vitro, sIL-4R biodistribution and elimination parameters were evaluated to assess the pharmacokinetic potential of sIL-4R as a therapeutic agent. Pharmacokinetic studies demonstrated that radiolabeled sIL-4R had a distribution half-life of 9 minutes and an elimination half-life of 2.3 hours following intravenous (IV) administration. When administered by intraperitoneal or subcutaneous (SC) injection, the elimination half- lives were prolonged to 4.2 hours and 6.2 hours, respectively. Although the initial blood level of sIL-4R was reduced if administered by SC injection, the bioavailability was comparable with IV administration. The main sites of sIL-4R elimination were the liver and kidney.

scholarly journals Schistosoma mansoni Hemozoin Modulates Alternative Activation of Macrophages via Specific Suppression of Retnla Expression and Secretion

2012 ◽  
Vol 81 (1) ◽  
pp. 133-142 ◽  
Author(s):  
Martha Truscott ◽  
D. Andrew Evans ◽  
Matt Gunn ◽  
Karl F. Hoffmann
Keyword(s):  
Schistosoma Mansoni ◽  
Macrophage Activation ◽  
Inflammatory Responses ◽  
Interleukin 4 ◽  
Alternative Activation ◽  
Content Type ◽  
Hepatic Expression ◽  
Life Years ◽  
Alternatively Activated

The trematodeSchistosoma mansoniis one of the etiological agents of schistosomiasis, a key neglected tropical disease responsible for an estimated annual loss of 70 million disability-adjusted life years. Hematophagy represents the primary nutrient acquisition pathway of this parasite, but digestion of hemoglobin also liberates toxic heme. Schistosomes detoxify heme via crystallization into hemozoin, which is subsequently regurgitated into the host's circulation. Here we demonstrate that during experimental schistosomiasis, hemozoin accumulating in the mouse liver is taken up by phagocytes at a time coincident with the development of the egg-induced T-helper 2 (Th2) granulomatous immune response. Furthermore, the uptake of hemozoin also coincides with the hepatic expression of markers of alternative macrophage activation. Alternatively activated macrophages are a key effector cell population associated with protection against schistosomiasis, making hemozoin well placed to play an important immunomodulatory role in this disease. To systematically explore this hypothesis,S. mansonihemozoin was purified and added toin vitrobone marrow-derived macrophage cultures concurrently exposed to cytokines chosen to reflect the shifting state of macrophage activationin vivo. Macrophages undergoing interleukin-4 (IL-4)-induced alternative activation in the presence of hemozoin developed a phenotype specifically lacking inRetnla, a characteristic alternatively activated macrophage product associated with regulation of Th2 inflammatory responses. As such, in addition to its important detoxification role during hematophagy, we propose that schistosome hemozoin also provides a potent immunomodulatory function in the coevolved network of host-parasite relationships during schistosomiasis.

scholarly journals Interleukin-4 (IL-4) enhances and soluble interleukin-4 receptor (sIL-4R) inhibits histamine release from peripheral blood basophils and mast cellsin vitroandin vivo

1997 ◽  
Vol 6 (2) ◽  
pp. 111-118 ◽  
Author(s):  
B. Niggemann ◽  
T. Zuberbier ◽  
U. Herz ◽  
K. Enssle ◽  
U. Wahn ◽  
...  
Keyword(s):  
Mast Cells ◽  
Histamine Release ◽  
Peripheral Blood ◽  
Specific Ige ◽  
Interleukin 4 ◽  
Effector Cells ◽  
Antibody Titres ◽  
Interleukin 4 Receptor

The aim of the study was to analyse the effect of interleukin-4 (IL-4) on allergen and anti-IgE mediated histamine release from basophils and human skin mast cells and to assess whether soluble recombinant interleukin-4 receptor (sIL4R) can inhibit these effects. Anti-IgE stimulated histamine release from peripheral blood basophils and mast cells of atopic donors was enhanced after preincubation with IL-4, whereas after preincubation with sIL-4R it was inhibited. These effects were even more pronounced when samples were stimulated with a clinically relevant allergen. In IL-4 preincubated skin mast cells, there was a similar enhancement of anti-IgE stimulated histamine release, which could again be inhibited by sIL-4R. The effects of IL-4 and sIL4R were dose- and time-dependent. Mice sensitized to ovalbumin and treated with soluble recombinant murine sIL-4R showed significantly reduced immediate-type cutaneous hypersensitivity responses compared with untreated mice. Thesein vivoeffects were IgE independent, since there were no significant differences in total and allergen specific IgE/IgG1 antibody titres between treated and untreated mice. This indicates that IL4 exerts priming effects on histamine release by effector cells of the allergic response and that these effects are potently antagonized by soluble IL-4R bothin vitroandin vivo.

scholarly journals Hodgkin lymphoma therapy with interleukin-4 receptor–directed cytotoxin in an infiltrating animal model

Blood ◽  
2005 ◽  
Vol 105 (9) ◽  
pp. 3707-3713 ◽  
Author(s):  
Mariko Kawakami ◽  
Koji Kawakami ◽  
Mitomu Kioi ◽  
Pamela Leland ◽  
Raj K. Puri
Keyword(s):  
Animal Model ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Interleukin 4 ◽  
Spontaneous Metastasis ◽  
Pseudomonas Exotoxin ◽  
Immunodeficient Mice ◽  
Interleukin 4 Receptor ◽  
Lymphoma Therapy

AbstractHodgkin lymphoma represents unique clinicopathologic features because Hodgkin and Reed-Sternberg (H-RS) cells produce a variety of cytokines, express a variety of cytokine receptors, and are surrounded by numerous nonmalignant immunoreactive cells. We found that receptors for interleukin-4 (IL-4R) are highly expressed in H-RS cells. To target interleukin-4 receptor (IL-4R), we used a recombinant protein fusing circularly permuted human IL-4 and Pseudomonas exotoxin termed IL438-37-PE38KDEL, or IL-4 cytotoxin. The cytotoxic effect of IL-4 cytotoxin on H-RS cell lines was determined to be moderate to high in vitro. We developed an infiltrating model of Hodgkin disease (HD) by injecting an adherent population of HD-MyZ cells subcutaneously into the flanks of beige/nude/X-linked immunodeficient mice. The animal model exhibited spontaneous metastasis of H-RS cells to lymph nodes and dissemination to vital organs, including the lungs. Intraperitoneal or intratumoral treatment of these mice with IL-4 cytotoxin resulted in regression of the primary tumor mass and a decrease in the incidence of lymph node metastasis. Mice injected with HD-MyZ cells demonstrated 203% prolonged survival (mean survival, 63 days) compared with control (mean survival, 31 days) when they received systemic IL-4 cytotoxin treatment. Because numerous H-RS cell lines express receptors for IL-4, IL-4 cytotoxin may be a unique agent for the treatment of Hodgkin lymphoma.

scholarly journals Netrin-1-treated macrophages protect the kidney against ischemia-reperfusion injury and suppress inflammation by inducing M2 polarization

2013 ◽  
Vol 304 (7) ◽  
pp. F948-F957 ◽  
Author(s):  
Punithavathi Vilapakkam Ranganathan ◽  
Calpurnia Jayakumar ◽  
Ganesan Ramesh
Keyword(s):  
Reperfusion Injury ◽  
Macrophage Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Kidney Injury ◽  
In Vitro Studies ◽  
Arginase 1 ◽  
M2 Polarization

Improper macrophage activation is pathogenically linked to various metabolic, inflammatory, and immune disorders. Therefore, regulatory proteins controlling macrophage activation have emerged as important new therapeutic targets. We recently demonstrated that netrin-1 regulates inflammation and infiltration of monocytes and ameliorates ischemia-reperfusion-induced kidney injury. However, it was not known whether netrin-1 regulates the phenotype of macrophages and the signaling mechanism through which it might do this. In this study, we report novel mechanisms underlying netrin-1's effects on macrophages using in vivo and in vitro studies. Overexpression of netrin-1 in spleen and kidney of transgenic mice increased expression of arginase-1, IL-4, and IL-13 and decreased expression of COX-2, indicating a phenotypic switch in macrophage polarization toward an M2-like phenotype. Moreover, flow cytometry analysis showed a significant increase in mannose receptor-positive macrophages in spleen compared with wild type. In vitro, netrin-1 induced the expression of M2 marker expression in bone marrow-derived macrophages, peritoneal macrophages, and RAW264.7 cells, and suppressed IFNγ-induced M1 polarization and production of inflammatory mediators. Adoptive transfer of netrin-1-treated macrophages suppressed inflammation and kidney injury against ischemia-reperfusion. Netrin-1 activated PPAR pathways and inhibition of PPAR activation abolished netrin-1-induced M2 polarization and suppression of cytokine production. Consistent with in vitro studies, administration of PPAR antagonist to mice abolished the netrin-1 protective effects against ischemia-reperfusion injury of the kidney. These findings illustrate that netrin-1 regulates macrophage polarization through PPAR pathways and confers anti-inflammatory actions in inflammed kidney tissue.

scholarly journals Network analysis reveals a distinct axis of macrophage activation in response to conflicting inflammatory cues

2019 ◽  
Author(s):  
Xiaji Liu ◽  
Jingyuan Zhang ◽  
Angela C. Zeigler ◽  
Anders R. Nelson ◽  
Merry L. Lindsey ◽  
...  
Keyword(s):  
Computational Model ◽  
Macrophage Activation ◽  
Expression Profiles ◽  
Interleukin 4 ◽  
Cytokine Signaling ◽  
Arginase 1 ◽  
M2 Polarization ◽  
Wide Range ◽  
Polarization Axis

AbstractMacrophages are subject to a wide range of cytokine and pathogen signals in vivo, which contribute to differential activation and modulation of inflammation. Understanding the response to multiple, often conflicting, cues that macrophages experience requires a network perspective. Here, we integrate data from literature curation and mRNA expression profiles to develop a large-scale computational model of the macrophage signaling network. In response to stimulation across all pairs of 9 cytokine inputs, the model predicted activation along the classic M1-M2 polarization axis but also a second axis of macrophage activation that distinguishes unstimulated macrophages from a mixed phenotype induced by conflicting cues. Along this second axis, combinations of conflicting stimuli, interleukin 4 (IL4) with lipopolysaccharide (LPS), interferon-γ (IFNγ), IFNβ, or tumor necrosis factor-α (TNFα), produced mutual inhibition of several signaling pathways, e.g. nuclear factor κB (NFκB) and signal transducer and activator of transcription 6 (STAT6), but also mutual activation of the phosphoinositide 3-kinases (PI3K) signaling module. In response to combined IFNγ and IL4, the model predicted genes whose expression was mutually inhibited, e.g. inducible nitric oxide synthase (iNOS) and arginase 1 (Arg1), or mutually enhanced, e.g. IL4 receptor-α (IL4Rα) and suppressor of cytokine signaling 1 (SOCS1), which was validated by independent experimental data. Knockdown simulations further predicted network mechanisms underlying functional crosstalk, such as mutual STAT3/STAT6-mediated enhancement of IL4Rα expression. In summary, the computational model predicts that network crosstalk mediates a broadened spectrum of macrophage activation in response to mixed pro- and anti-inflammatory cytokine cues, making it useful for modeling in vivo scenarios.Summary sentenceNetwork modeling of macrophage activation predicts responses to combinations of cytokines along both the M1-M2 polarization axis and a second axis associated with a mixed macrophage activation phenotype.

scholarly journals Targeting Interleukin-4 Receptor Alpha by Hybrid Peptide for Novel Biliary Tract Cancer Therapy

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Kahori Seto ◽  
Junichi Shoda ◽  
Tomohisa Horibe ◽  
Eiji Warabi ◽  
Masayuki Kohno ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cytotoxic Activity ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Interleukin 4 ◽  
Hybrid Peptide ◽  
Tract Cancer ◽  
Interleukin 4 Receptor

It is known that the interleukin-4 receptorα(IL-4Rα) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4Rα-lytic hybrid peptide composed of binding peptide to IL-4Rαand cell-lytic peptide and reported that the designed IL-4Rα-lytic hybrid peptide exhibited cytotoxic and antitumor activity bothin vitroandin vivoagainst the human pancreatic cancer cells expressing IL-4Rα. Here, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC). The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50) as low as 5 μM. We also showed that IL-4Rα-lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activityin vitro. In addition, intravenous administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTCin vivo. Taken together, these results indicated that the IL-4Rα-lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC.

scholarly journals Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype

2020 ◽  
Vol 8 (1) ◽  
pp. e000339 ◽  
Author(s):  
Hongliang Dong ◽  
Yueyao Yang ◽  
Chenhui Gao ◽  
Hehe Sun ◽  
Hongmin Wang ◽  
...  
Keyword(s):  
Protective Efficacy ◽  
Suppressor Cells ◽  
Interleukin 10 ◽  
Interleukin 4 ◽  
Tumor Associated Macrophages ◽  
Antitumor Effects ◽  
Tumoricidal Activity ◽  
Arginase 1

BackgroundTumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy.MethodsA mouse IgG1(kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14+monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models.ResultsThrough coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues.ConclusionsLTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.

scholarly journals Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1848-1857 ◽  
Author(s):  
PW Johnson ◽  
SM Watt ◽  
DR Betts ◽  
D Davies ◽  
S Jordan ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Lymphocytes ◽  
B Cell Lymphoma ◽  
Germinal Centers ◽  
Interleukin 4 ◽  
Low Grade ◽  
Lymphoma Cells ◽  
Karyotypic Analysis ◽  
Hodgkin's Lymphomas

Abstract Low-grade follicular non-Hodgkin's lymphomas are characterized by the presence of a t(14;18) chromosomal translocation that results in deregulation of the B-cell lymphoma (Bcl-2) gene. Studies in cell lines and transgenic animal models have suggested that this results in the suppression of apoptotic cell death in germinal centers. B lymphocytes from normal germinal centers and lymph nodes infiltrated by follicular lymphoma were isolated by immunomagnetic depletion of cells bearing CD4, CD8, or slgD for study in vitro. Follicular lymphoma cells expressing Bcl-2 protein were shown to resist apoptosis after isolation, and could be induced to proliferate in a culture system previously described for the growth of normal B lymphocytes. By the use of a mouse fibroblast monolayer transfected with the CDw32 Fc receptor to present CD40 monoclonal antibody in the presence of interleukin-4, prolonged culture was possible. Karyotypic analysis of cultured lymphoma cells showed the t(14;18) translocation, with clonal identity confirmed by polymerase chain reaction amplification of the breakpoints and direct sequence analysis. These findings support the hypothesis that resistance to apoptosis is an influence on the initiation of follicular lymphoma, and provide a novel means of studying in vitro the intercellular reactions that may be important in progression of the disease.

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