scholarly journals Gas6 Induces Myelination through Anti-Inflammatory IL-10 and TGF-β Upregulation in White Matter and Glia

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1779
Author(s):  
Salman Goudarzi ◽  
Shannon E. Gilchrist ◽  
Sassan Hafizi
Keyword(s):  
Optic Nerve ◽  
Glial Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Therapeutic Interventions ◽  
High Expression ◽  
Receptor System ◽  
Tam Receptors ◽  
Anti Inflammatory

The Gas6–TAM (Tyro3, Axl, Mer) ligand–receptor system is believed to promote central nervous system (CNS) (re)myelination and glial cell development. An additional important function of Gas6–TAM signalling appears to be the regulation of immunity and inflammation, which remains to be fully elucidated in the CNS. Here, we characterised the expression of TAM receptors and ligands in individual CNS glial cell types, observing high expression of Gas6 and the TAM receptors, Mer and Axl, in microglia, and high expression of Tyro3 in astrocytes. We also investigated the effect of Gas6 on the inflammatory cytokine response in the optic nerve and in mixed glial cell cultures from wildtype and single TAM receptor knockout mice. In wildtype and Mer-deficient cultures, Gas6 significantly stimulated the expression of the anti-inflammatory/pro-repair cytokines interleukin 10 (IL-10) and transforming growth factor β (TGF-β), whereas this effect was absent in either Tyro3 or Axl knockout cultures. Furthermore, Gas6 caused upregulation of myelin basic protein (MBP) expression in optic nerves, which was blocked by a neutralising antibody against IL-10. In conclusion, our data show that microglia are both a major source of Gas6 as well as an effector of Gas6 action in the CNS through the upregulation of anti-inflammatory and pro-repair mediators. Furthermore, the presence of both Axl and Tyro3 receptors appears to be necessary for these effects of Gas6. In addition, IL-10, alongside suppressing inflammation and immunity, mediates the pro-myelinating mechanism of Gas6 action in the optic nerve. Therefore, Gas6 may present an attractive target for novel therapeutic interventions for demyelinating as well as neuroinflammatory disorders of the CNS.

scholarly journals Controlling Gut Inflammation by Restoring Anti-Inflammatory Pathways in Inflammatory Bowel Disease

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 397 ◽  
Author(s):  
Paolo Giuffrida ◽  
Sara Cococcia ◽  
Mariangela Delliponti ◽  
Marco Vincenzo Lenti ◽  
Antonio Di Sabatino
Keyword(s):  
Inflammatory Bowel Disease ◽  
Side Effects ◽  
Bowel Disease ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Interleukin 12 ◽  
Inflammatory Pathways ◽  
Inflammatory Bowel ◽  
Anti Inflammatory

Inflammatory bowel disease (IBD) is caused by a dysregulated immune response against normal components of the intestinal microflora combined with defective functioning of anti-inflammatory pathways. Currently, all therapies approved for IBD manipulate the immune system by inhibiting pro-inflammatory mechanisms, such as tumor necrosis factor-α, gut-homing α4β7 integrin, interleukin-12/interleukin-23, and Janus kinases. However, some IBD patients are non-responders to these drugs, which are also associated with serious side effects. Thus, it has been hypothesized that therapies aimed at restoring anti-inflammatory signals, by exploiting the tolerogenic potential of cytokines (interleukin-10, transforming growth factor-β, granulocyte macrophage colony-stimulating factor), immune cells (regulatory T cells, tolerogenic dendritic cells), or mesenchymal stem cells, might offer promising results in terms of clinical efficacy with fewer side effects. In this review, we provide new insights into putative novel treatments aimed at restoring anti-inflammatory signaling pathways in IBD.

scholarly journals TGF-β/TGF-β receptor system and its role in physiological and pathological conditions

2011 ◽  
Vol 121 (6) ◽  
pp. 233-251 ◽  
Author(s):  
Juan F. Santibañez ◽  
Miguel Quintanilla ◽  
Carmelo Bernabeu
Keyword(s):  
Transforming Growth Factor ◽  
Adult Stem Cell ◽  
Stem Cell Differentiation ◽  
Transforming Growth Factor Β ◽  
Therapeutic Interventions ◽  
Receptor System ◽  
Congenital Diseases ◽  
Cardiovascular Pathology ◽  
Pathological Conditions ◽  
Β Receptor

The TGF-β (transforming growth factor-β) system signals via protein kinase receptors and Smad mediators to regulate a plethora of biological processes, including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. In addition, alterations of specific components of the TGF-β signalling pathway may contribute to a broad range of pathologies such as cancer, cardiovascular pathology, fibrosis and congenital diseases. The knowledge about the mechanisms involved in TGF-β signal transduction has allowed a better understanding of the disease pathogenicity as well as the identification of several molecular targets with great potential in therapeutic interventions.

scholarly journals Myeloid-Derived Suppressor Cells Evolve during Sepsis and Can Enhance or Attenuate the Systemic Inflammatory Response

2012 ◽  
Vol 80 (6) ◽  
pp. 2026-2034 ◽  
Author(s):  
Laura Brudecki ◽  
Donald A. Ferguson ◽  
Charles E. McCall ◽  
Mohamed El Gazzar
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Cecal Ligation ◽  
Suppressor Cells ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Myeloid Derived Suppressor Cells ◽  
Inflammatory Conditions ◽  
Anti Inflammatory

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are a heterogeneous Gr1+CD11b+population of immature cells containing granulocytic and monocytic progenitors, which expand under nearly all inflammatory conditions and are potent repressors of T-cell responses. Studies of MDSCs during inflammatory responses, including sepsis, suggest they can protect or injure. Here, we investigated MDSCs during early and late sepsis. To do this, we used our published murine model of cecal ligation and puncture (CLP)-induced polymicrobial sepsis, which transitions from an early proinflammatory phase to a late anti-inflammatory and immunosuppressive phase. We confirmed that Gr1+CD11b+MDSCs gradually increase after CLP, reaching ∼88% of the bone marrow myeloid series in late sepsis. Adoptive transfer of early (day 3) MDSCs from septic mice into naive mice after CLP increased proinflammatory cytokine production, decreased peritoneal bacterial growth, and increased early mortality. Conversely, transfer of late (day 12) MDSCs from septic mice had the opposite effects. Early and late MDSCs studiedex vivoalso differed in their inflammatory phenotypes. Early MDSCs expressed nitric oxide and proinflammatory cytokines, whereas late MDSCs expressed arginase activity and anti-inflammatory interleukin 10 (IL-10) and transforming growth factor β (TGF-β). Late MDSCs had more immature CD31+myeloid progenitors and, when treatedex vivowith granulocyte-macrophage colony-stimulating factor (GM-CSF), generated fewer macrophages and dendritic cells than early MDSCs. We conclude that as the sepsis inflammatory process progresses, the heterogeneous MDSCs shift to a more immature state and from being proinflammatory to anti-inflammatory.

P–418 Different immunoregulatory components at the decidua basalis of oocyte donation pregnancies

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
K Va. Bentem ◽  
M Bos ◽  
C Va. de. Keur ◽  
H Kapsenberg ◽  
L Lashley ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Hla Class I ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Oocyte Donation ◽  
Class I ◽  
Decidua Basalis ◽  
Immunoregulatory Cytokines ◽  
Maternal Peripheral Blood ◽  
Hla Mismatches

Abstract Study question Is the number of regulatory T-cells (Tregs) and immunoregulatory cytokines in the decidua basalis of oocyte donation (OD) pregnancies different compared to naturally conceived pregnancies? Summary answer This study suggests that the immunoregulation at the fetal-maternal interface in OD pregnancies with a higher amount of fetal-maternal HLA mismatches appears to be altered. What is known already Tregs and related immunoregulatory cytokines, such as interleukins, transforming growth factor-β, and galectin–1, play a key role in maintaining tolerance at the decidua basalis in human pregnancy. Previous studies observed decreased numbers of decidual Tregs in miscarriage and preeclamptic pregnancies. These complications occur in higher frequencies in OD pregnancies, which are characterized by more fetal-maternal human leukocyte antigen (HLA) mismatches compared with naturally conceived (NC) and non-donor in vitro fertilization (IVF) pregnancies, since the fetus obtains paternal and donor-derived HLA genes. Consequently, the maternal immune system has to cope with greater immunogenetic dissimilarity. Involved immunoregulatory mechanisms however remain poorly understood. Study design, size, duration: This case-control study included 27 OD, 11 IVF, and 16 NC placentas of uncomplicated pregnancies, which were collected after delivery at 37–42 weeks of gestation between 2005 and 2013. Clinical data, maternal peripheral blood and umbilical cord blood were collected. Participants/materials, setting, methods Decidua basalis was dissected from the placentas, and processed to formalin-fixed, paraffin-embedded slices (4 µm). Immunohistochemical staining for FOXP3, interleukin 10, interleukin 6, galectin–1, transforming growth factor-β, and Flt–1 was performed. Semi-quantitative (FOXP3+ Tregs) and computerized analysis (cytokines), using Image-J software, were executed. Maternal peripheral blood and fetal umbilical cord blood were typed for HLA class I and II, using the Sequence Specific Oligonucleotides PCR technique, to calculate the number of fetal-maternal HLA mismatches. Main results and the role of chance All the deciduae basalis of OD, IVF and NC pregnancies showed FOXP3+ Tregs. No significant differences were found when comparing the three groups for the mean number of FOXP3+ Tregs. However, when the amount of fetal-maternal HLA mismatches was related to the percentage of FOXP3+ Tregs, the Tregs were significantly higher in pregnancies with 4–6 HLA class I mismatches (n = 16), than in those with 0–3 HLA class I mismatches (n = 38; p = 0.029). Furthermore, OD pregnancies express less interleukin 10, interleukin 6, galectin–1 and Flt–1 in the decidua basalis compared to NC pregnancies. Moreover, the amount of interleukin 10 was significantly lower with 3–4 fetal-maternal HLA class II mismatches (p = 0.032). Limitations, reasons for caution This study is limited by a small sample size. Moreover, only term placentas were collected. It would be worthwhile investigating immunological alterations in the decidua throughout the whole gestation, since maternal adaptation of the fetal allograft could be more prominent early in pregnancy. Wider implications of the findings: Unravelling the mechanisms of immunomodulation during OD pregnancy, reflected by a high level of fetal-maternal dissimilarity, could help to reach the ultimate goal in transplantation; the induction of donor-specific tolerance. In addition, it might help to understand the development of complications in OD pregnancy. Trial registration number Not applicable

scholarly journals Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inf lammation

2003 ◽  
Vol 198 (10) ◽  
pp. 1517-1525 ◽  
Author(s):  
Arihiro Kano ◽  
Michael J. Wolfgang ◽  
Qian Gao ◽  
Joerg Jacoby ◽  
Gui-Xuan Chai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Endotoxic Shock ◽  
Transforming Growth Factor Β ◽  
Organ Damage ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Protective Function ◽  
Lps Challenge

Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3E−/−). STAT3E−/− mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3E−/− mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.

scholarly journals Local and systemic influence of toxic levels of airborne ozone on the inflammatory response in rats

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Małgorzata Chmielewska-Krzesińska ◽  
Krzysztof Wąsowicz
Keyword(s):  
Inflammatory Response ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Genes Expression ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

Abstract Introduction Ozone is not harmful itself; however, it directly oxidises biomolecules and produces radical-dependent cytotoxicity. Exposure to ozone is by inhalation and therefore the lungs develop the main anti-inflammatory response, while ozone has an indirect impact on the other organs. This study investigated the local and systemic effects of the ozone-associated inflammatory response. Material and Methods Three groups each of 5 Wistar Han rats aged 6 months were exposed for 2h to airborne ozone at 0.5 ppm and a fourth identical group were unexposed controls. Sacrifice was at 3h after exposure for control rats and one experimental group and at 24 h and 48 h for the others. Lung and liver samples were evaluated for changes in expression of transforming growth factor beta 1, anti-inflammatory interleukin 10, pro-inflammatory tumour necrosis factor alpha and interleukin 1 beta and two nuclear factor kappa-light-chain-enhancer of B cells subunit genes. Total RNA was isolated from the samples in spin columns and cDNA was synthesised in an RT-PCR. Expression levels were compared to those of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and analysed statistically. Results All variables changed non-linearly over time comparing experimental groups to the control. Conspicuous expression changes in the subunit genes and cytokines were observed in both evaluated organs. Conclusion Locally and systemically, inflammation responses to ozone inhalation include regulation of certain genes’ expression. The mechanisms are unalike in lungs and liver but ozone exerts a similar effect in both organs. A broader range of variables influential on ozone response should be studied in the future.

scholarly journals Effects of Gamma Interferon, Interleukin-10, and Transforming Growth Factor β on the Survival of Mycobacterium avium subsp. paratuberculosis in Monocyte-Derived Macrophages from Naturally Infected Cattle

2004 ◽  
Vol 72 (4) ◽  
pp. 1974-1982 ◽  
Author(s):  
M. S. Khalifeh ◽  
J. R. Stabel
Keyword(s):  
Growth Factor ◽  
Cell Cultures ◽  
Mycobacterium Avium ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Ifn Γ ◽  
Culture Supernatants

ABSTRACT Gamma interferon (IFN-γ) plays a significant role in the control of mycobacterial infections, including Mycobacterium avium subsp. paratuberculosis. However, the contribution of other immunoregulatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor β (TGF-β), in Johne's disease has not been investigated as yet. In this study, we examined the effects of in vivo and in vitro infection with M. avium subsp. paratuberculosis on the production of IFN-γ, IL-10, and TGF-β by peripheral blood mononuclear cells (PBMC). We also examined the effects of exogenous IFN-γ, IL-10, and TGF-β on M. avium subsp. paratuberculosis survival in the cell cultures. PBMC obtained from naturally infected cows, regardless of their disease status, specifically upregulated IL-10 and TGF-β in culture supernatants in response to stimulation with live M. avium subsp. paratuberculosis. Nonstimulated PBMC recovered from subclinically infected animals secreted the lowest levels of TGF-β, but after stimulation with live M. avium subsp. paratuberculosis, TGF-β levels in the culture supernatants increased to levels similar to that produced by PBMC from healthy animals. The numbers of viable M. avium subsp. paratuberculosis recovered from cultures from naturally infected animals were higher than those from healthy cows after in vitro infection with M. avium subsp. paratuberculosis. The addition of exogenous IL-10 and TGF-β to PBMC isolated from healthy cows inhibited the bactericidal activity of these cells as evidenced by the increased number of viable M. avium subsp. paratuberculosis recovered from these cultures compared to cell cultures containing medium alone. These data suggest important immune regulatory roles for IL-10 and TGF-β during infection with M. avium subsp. paratuberculosis that may be directly related to their effects on macrophage activation and killing of M. avium subsp. paratuberculosis.

Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials

2018 ◽  
Vol 10 (422) ◽  
pp. eaao0475 ◽  
Author(s):  
Marsha C. Lampi ◽  
Cynthia A. Reinhart-King
Keyword(s):  
Extracellular Matrix ◽  
Clinical Trials ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Therapeutic Interventions ◽  
Target Tissue ◽  
Matrix Stiffness ◽  
Extracellular Matrix Stiffness

Tissues stiffen during aging and during the pathological progression of cancer, fibrosis, and cardiovascular disease. Extracellular matrix stiffness is emerging as a prominent mechanical cue that precedes disease and drives its progression by altering cellular behaviors. Targeting extracellular matrix mechanics, by preventing or reversing tissue stiffening or interrupting the cellular response, is a therapeutic approach with clinical potential. Major drivers of changes to the mechanical properties of the extracellular matrix include phenotypically converted myofibroblasts, transforming growth factor β (TGFβ), and matrix cross-linking. Potential pharmacological interventions to overcome extracellular matrix stiffening are emerging clinically. Aside from targeting stiffening directly, alternative approaches to mitigate the effects of increased matrix stiffness aim to identify and inhibit the downstream cellular response to matrix stiffness. Therapeutic interventions that target tissue stiffening are discussed in the context of their limitations, preclinical drug development efforts, and clinical trials.

scholarly journals Inflammatory cytokines in the pathogenesis of cardiovascular disease and cancer

2020 ◽  
Vol 8 ◽  
pp. 205031212096575 ◽  
Author(s):  
Mohammad Nurul Amin ◽  
Shafayet Ahmed Siddiqui ◽  
Md Ibrahim ◽  
Md Lukman Hakim ◽  
Md. Salim Ahammed ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Inflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Transforming Growth Factor Β ◽  
Causative Factor ◽  
Interleukin 10 ◽  
Cardiac Events ◽  
Human Immune System ◽  
Cancer Pathogenesis

Inflammatory cytokines are highly inducible small glycoproteins or regulatory proteins of low molecular weight secreted by different cell types. They regulate intercellular communication and mediate a number of physiological functions in the human immune system. Numerous prospective studies report that inflammatory cytokines strongly predict coronary artery disease, myocardial infarction, heart failure and other adverse cardiac events. Inflammatory cascade is believed to be a causative factor in the development of atherosclerotic process. Several aspects of atherogenesis are accelerated by cytokines. This article provides an overall overview of current understanding of cytokines in various cardiovascular events. Besides, inflammatory cytokines trigger cellular events that can induce malignancy and carcinogenesis. Elevated expression of several cytokines such as interleukin-1, interleukin-6, interleukin-10, tumor necrosis factor-α, macrophage migration inhibitory factor and transforming growth factor-β are involved in tumor initiation and progression. Thus, they exert a pivotal role in cancer pathogenesis. This review highlights the role of several cytokines in various events of tumorigenesis. Actually, this article summarizes the contributions of cytokines in the pathogenesis of cardiovascular disease and cancer.

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