scholarly journals Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair

2020 ◽  
Vol 7 (2) ◽  
pp. 33 ◽  
Author(s):  
Jiranuwat Sapudom ◽  
Walaa Kamal E. Mohamed ◽  
Anna Garcia-Sabaté ◽  
Aseel Alatoom ◽  
Shaza Karaman ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Collagen Fibril ◽  
Tissue Repair ◽  
Macrophage Activation ◽  
Transforming Growth Factor ◽  
Culture Media ◽  
Interleukin 4 ◽  
Cellular Functions ◽  
Tissue Density ◽  
Inflammatory Macrophages

Monocytes circulate in the bloodstream, extravasate into the tissue and differentiate into specific macrophage phenotypes to fulfill the immunological needs of tissues. During the tissue repair process, tissue density transits from loose to dense tissue. However, little is known on how changes in tissue density affects macrophage activation and their cellular functions. In this work, monocytic cell line THP-1 cells were embedded in three-dimensional (3D) collagen matrices with different fibril density and were then differentiated into uncommitted macrophages (MPMA) using phorbol-12-myristate-13-acetate (PMA). MPMA macrophages were subsequently activated into pro-inflammatory macrophages (MLPS/IFNγ) and anti-inflammatory macrophages (MIL-4/IL-13) using lipopolysaccharide and interferon-gamma (IFNγ), and interleukin 4 (IL-4) and IL-13, respectively. Although analysis of cell surface markers, on both gene and protein levels, was inconclusive, cytokine secretion profiles, however, demonstrated differences in macrophage phenotype. In the presence of differentiation activators, MLPS/IFNγ secreted high amounts of IL-1β and tumor necrosis factor alpha (TNFα), while M0PMA secreted similar cytokines to MIL-4/IL-13, but low IL-8. After removing the activators and further culture for 3 days in fresh cell culture media, the secretion of IL-6 was found in high concentrations by MIL-4/IL-13, followed by MLPS/IFNγ and MPMA. Interestingly, the secretion of cytokines is enhanced with an increase of fibril density. Through the investigation of macrophage-associated functions during tissue repair, we demonstrated that M1LPS/IFNγ has the potential to enhance monocyte infiltration into tissue, while MIL-4/IL-13 supported fibroblast differentiation into myofibroblasts via transforming growth factor beta 1 (TGF-β1) in dependence of fibril density, suggesting a M2a-like phenotype. Overall, our results suggest that collagen fibril density can modulate macrophage response to favor tissue functions. Understanding of immune response in such complex 3D microenvironments will contribute to the novel therapeutic strategies for improving tissue repair, as well as guidance of the design of immune-modulated materials.

scholarly journals Foxp3+ T Regulatory Cells as a Potential Target for Immunotherapy against Primary Infection with Echinococcus multilocularis Eggs

2018 ◽  
Vol 86 (10) ◽  
Author(s):  
Junhua Wang ◽  
Rita Cardoso ◽  
Nelson Marreros ◽  
Norbert Müller ◽  
Britta Lundström-Stadelmann ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Echinococcus Multilocularis ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Expression Profiles ◽  
Growth Potential ◽  
Interleukin 4 ◽  
Content Type ◽  
Hepatic Expression ◽  
Th2 Immune Response

ABSTRACT Alveolar echinococcosis (AE) is a lethal disease caused by infection with the metacestode stage of the helminth Echinococcus multilocularis, which develops into a tumorlike mass in susceptible intermediate hosts. The growth potential of this parasite stage is directly linked to the nature of the surrounding periparasitic immune-mediated processes. In a first step (experiment 1), mice were orally infected with E. multilocularis eggs, to be used for assessing the hepatic expression profiles of 15 selected cytokine and chemokine genes related to acquired immunity from 21 to 120 days postinfection. The early stage of infection in immunocompetent animals was marked by a mixed Th1/Th2 immune response, as characterized by the concomitant presence of gamma interferon (IFN-γ) and interleukin-4 (IL-4) and their related chemokines. At the late stage of AE, the profile extended to a combined tolerogenic mode including Foxp3, IL-10, and transforming growth factor beta (TGF-β) as key components. In a second step (experiment 2), the effect of T regulatory cell (Treg) deficiency on metacestode growth was assessed in E. multilocularis-infected DEREG (depletion of regulatory T cells) mice upon induction of Treg deficiency with diphtheria toxin (DT). The parasite lesions were significantly smaller in the livers of treated mice than in corresponding control groups. Foxp3+ Tregs appear to be one of the key players in immune-regulatory processes favoring metacestode survival by affecting antigen presentation and suppressing Th1-type immune responses. For these reasons, we suggest that affecting Foxp3+ Tregs could offer an attractive target in the development of an immunotherapy against AE.

scholarly journals Enhanced expression of transforming growth factor beta during megakaryoblastic differentiation of K562 leukemia cells

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 899-906
Author(s):  
R Alitalo ◽  
TP Makela ◽  
P Koskinen ◽  
LC Andersson ◽  
K Alitalo
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Culture Media ◽  
Tissue Injury ◽  
Leukemia Cell ◽  
K562 Cells ◽  
Leukemia Cell Line ◽  
Tgf Beta ◽  
Growth Factor Beta

Platelet alpha granules contain several growth factors such as the transforming growth factor beta (TGF-beta) that are released during blood clotting and are thought to participate in the repair of tissue injury; however, the site of synthesis of platelet TGF-beta has not been demonstrated. We studied TGF-beta expression during megakaryoblastic differentiation of the chronic myeloid leukemia cell line K562 in vitro. These cells have mainly erythroid characteristics but acquire several megakaryoblastic properties when treated with the phorbol diester 12–0-tetradecanoyl-13-phorbolacetate (TPA). During four subsequent days of megakaryoblastic differentiation the amount of the 2.5-kilobase (kb) TGF-beta mRNA increased about eightfold, and a novel 2.3-kb mRNA species was induced in the K562 cells. This occurred concomitantly with distinct induction patterns of platelet-derived growth factor A (PDGF-A) and c-sis (PDGF-B chain) RNAs and several platelet antigens. The expression of erythroid markers such as glycophorin A decreased. Culture media of TPA-differentiated K562 cells also contained TGF-beta polypeptides as shown by a sensitive radioreceptor assay and by immunoprecipitation after metabolic labeling of the cells. These polypeptides were not seen in culture media from dimethyl sulfoxide- or sodium butyrate-treated cells. Unlike in several other cells, exogenously added TGF-beta 1 or 2 affected neither TGF- beta nor PDGF RNA expression in K562 cells.

scholarly journals Human interleukin-4 inhibits proliferation of megakaryocyte progenitor cells in culture

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 624-630 ◽  
Author(s):  
Y Sonoda ◽  
Y Kuzuyama ◽  
S Tanaka ◽  
S Yokota ◽  
T Maekawa ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Colony Formation ◽  
Neutralizing Antibodies ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Interleukin 4 ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Necrosis Factor Alpha

Abstract We studied the effects of recombinant human interleukin-4 (rhIL-4) on megakaryocyte colony formation from enriched hematopoietic progenitors. IL-4 strongly inhibited pure and mixed megakaryocyte colony formation in a dose-dependent manner. Formation of erythroid bursts, eosinophil colonies, and erythrocyte-containing mixed colonies was not affected by the addition of IL-4 as reported previously (Sonoda Y, et al; Blood 75:1615, 1990). Delayed addition experiments suggested that IL-4 acts on an early stage of proliferation of megakaryocyte progenitors. Neutralizing antibodies (antisera) prepared against transforming growth factor beta, tumor necrosis factor alpha, interferon alpha (IFN alpha), and IFN gamma did not affect the inhibitory effects of IL-4 on pure and mixed megakaryocyte colony formation. In addition, the inhibitory effects of IL-4 was also seen in serum-free cultures and in cultures containing highly enriched CD34+, HLA-DR+ cells as a target population. These results indicate that IL-4 may function as one of the negative regulators in human megakaryocytopoiesis in vitro.

scholarly journals Anti-inflammatory response of IL-4, IL-10 and TGF-β in patients with systemic inflammatory response syndrome

2000 ◽  
Vol 9 (3-4) ◽  
pp. 193-195 ◽  
Author(s):  
Donato Torre ◽  
Roberto Tambini ◽  
Silvana Aristodemo ◽  
Giovanna Gavazzeni ◽  
Antonio Goglio ◽  
...  
Keyword(s):  
Systemic Inflammatory Response Syndrome ◽  
Inflammatory Response ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Serum Levels ◽  
Interleukin 10 ◽  
Systemic Inflammatory Response ◽  
Interleukin 4 ◽  
Significant Difference ◽  
Anti Inflammatory

The systemic inflammatory response syndrome (SIRS) is an inflammatory process seen in association with a large number of clinical infective and noninfective conditions.The aim of this study was to investigate the role of anti-inflammatory cytokines such as interleukin–4 (IL–4), interleukin–10 (IL–10), and transforming growth factor-beta (TGF-beta). Serum levels of IL–4, IL–10 and TGF-β were determined in 45 patients with SIRS: 38 patients had SIRS of infectious origin, whereas seven patients had non-infectious SIRS. Twenty healthy subjects were used as controls.Serum levels of IL–4, IL–10 and TGFg were determined by an immunoenzyme assay. A significant increase of IL–4 was observed in these patients at the time of diagnosis and 5 days later. In contrast, serum levels of IL–10 were not increased at the time of diagnosis, but a slight decrease was noted after 5 days. Serum levels of TGF-β were not increased at time of diagnosis, and a slight increase was observed after 5 days. Serum levels of IL–4 were significantly higher in patients with infectious SIRS at the time of diagnosis, whereas no significant difference between infectious and non-infectious SIRS was noted for serum levels of IL–10 and TGF-β at the time of diagnosis and 5 days later.During SIRS, serum levels of IL–4 were significantly increased with a significant correlation between IL–4 and mortality, and only levels of IL–4 were significantly increased in the SIRS caused by infectious stimuli.

scholarly journals Interacting cytokines regulate in vitro human megakaryocytopoiesis

Blood ◽  
1989 ◽  
Vol 73 (3) ◽  
pp. 671-677 ◽  
Author(s):  
E Bruno ◽  
ME Miller ◽  
R Hoffman
Keyword(s):  
Transforming Growth Factor Beta ◽  
Colony Formation ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Interleukin 4 ◽  
Recombinant Erythropoietin ◽  
Hematopoietic Growth Factors ◽  
Macrophage Colony ◽  
Stimulating Factor

The effects of hematopoietic growth factors on in vitro human megakaryocytopoiesis were studied using a serum-depleted culture system. Both recombinant interleukin-3 (r-IL-3) and recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) increased megakaryocyte (MK) colony formation (P less than .01) above that observed in baseline cultures. Recombinant interleukin-4 (rIL-4) and interleukin 1 alpha (rIL-1 alpha) failed either to promote MK colony formation alone or to increase rIL-3 or rGM-CSF promoted colony formation. Recombinant erythropoietin (rEpo) and purified thrombocytopoiesis-stimulating factor (TSF) did not increase (P greater than .05) MK colony formation when added alone but synergized with rIL- 1 alpha, leading to a twofold increase in MK colony formation. Such a synergistic relationship was not observed between rIL-4 and rEpo. In addition, TSF enhanced the ability of rIL-3 but not rGM-CSF to promote MK colony formation. Addition of rEpo to optimal or suboptimal concentrations of rGM-CSF or suboptimal concentrations of rIL-3 resulted in a significant increase (P less than .05) in the total number of MK-containing colonies, due to the appearance of multilineage colonies containing MKs. The addition of rEpo to optimal concentrations of rIL-3 resulted in increased numbers of multilineage colonies containing MKs; however, the number of total MK-containing colonies was not significantly increased when compared to assays containing rIL-3 alone. By contrast, transforming growth factor-beta (TGF-beta) inhibited both rIL-3, and rGM-CSF promoted MK colony formation, with optimal inhibition resulting in a 35%-45% reduction of MK colony formation.

scholarly journals Transforming growth factor beta (TGF-beta), a potent inhibitor of erythropoiesis: neutralizing TGF-beta antibodies show erythropoietin as a potent stimulator of murine burst-forming unit erythroid colony formation in the absence of a burst-promoting activity

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 949-957 ◽  
Author(s):  
I Dybedal ◽  
SE Jacobsen
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Colony Formation ◽  
Transforming Growth Factor ◽  
Interleukin 4 ◽  
Assay Method ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tgf Beta ◽  
Erythroid Progenitors ◽  
Growth Factor Beta

Abstract Transforming growth factor beta (TGF-beta) is a bifunctional regulator of the growth of myeloid progenitors and is here demonstrated to directly inhibit the growth of primitive erythroid progenitors by 95% to 100% regardless of the cytokines stimulating growth. Autocrine TGF- beta production of primitive hematopoietic progenitors has previously been reported. In the present study, a neutralizing TGF-beta antibody (anti-TGF-beta) added to serum-containing cultures, resulted in a 3-, 4- , and 25-fold increase in burst-forming unit erythroid (BFU-E) colony formation in response to interleukin-4 (IL-4) plus erythropoietin (Epo), SCF plus Epo, and IL-11 plus Epo, respectively. The growth of BFU-E progenitors has been suggested to require a burst-promoting activity in addition to Epo. Accordingly, we observed no BFU-E colony formation in serum-containing cultures in response to Epo alone. In contrast, 50 BFU-E colonies were formed when anti-TGF-beta was included in the culture. In serum-free cultures, Epo also stimulated BFU-E colony formation in the absence of other cytokines, whereas anti-TGF- beta had no effect on the number of colonies formed. Quantitation of TGF-beta 1 in serum by an enzyme-linked immunosorbent assay method showed predominantly the presence of precursor (latent) TGF-beta 1, but also showed active TGF-beta 1 at a concentration sufficient to potently inhibit erythroid colony formation. Thus, neutralization of active TGF- beta 1 in serum shows that Epo alone is sufficient to stimulate the growth of murine BFU-E progenitors.

scholarly journals Cytokine Profile in Striated Muscle Laminopathies: New Promising Biomarkers for Disease Prediction

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1532
Author(s):  
Cristina Cappelletti ◽  
Irene Tramacere ◽  
Paola Cavalcante ◽  
Elisa Schena ◽  
Luisa Politano ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Striated Muscle ◽  
Wide Spectrum ◽  
Serum Levels ◽  
Interleukin 4 ◽  
Interleukin 17 ◽  
Lmna Gene ◽  
New Therapeutic Approaches ◽  
Inflammatory Molecules

Laminopathies are a wide and heterogeneous group of rare human diseases caused by mutations of the LMNA gene or related nuclear envelope genes. The variety of clinical phenotypes and the wide spectrum of histopathological changes among patients carrying an identical mutation in the LMNA gene make the prognostic process rather difficult, and classical genetic screens appear to have limited predictive value for disease development. The aim of this study was to evaluate whether a comprehensive profile of circulating cytokines may be a useful tool to differentiate and stratify disease subgroups, support clinical follow-ups and contribute to new therapeutic approaches. Serum levels of 51 pro- and anti-inflammatory molecules, including cytokines, chemokines and growth factors, were quantified by a Luminex multiple immune-assay in 53 patients with muscular laminopathy (Musc-LMNA), 10 with non-muscular laminopathy, 22 with other muscular disorders and in 35 healthy controls. Interleukin-17 (IL-17), granulocyte colony-stimulating factor (G-CSF) and transforming growth factor beta (TGF-β2) levels significantly discriminated Musc-LMNA from controls; interleukin-1β (IL-1β), interleukin-4 (IL-4) and interleukin-8 (IL-8) were differentially expressed in Musc-LMNA patients compared to those with non-muscular laminopathies, whereas IL-17 was significantly higher in Musc-LMNA patients with muscular and cardiac involvement. These findings support the hypothesis of a key role of the immune system in Musc-LMNA and emphasize the potential use of cytokines as biomarkers for these disorders.

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