Retinoic acid is a negative regulator for the differentiation of cord blood-derived human mast cell progenitors

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2821-2828 ◽  
Author(s):  
Tatsuya Kinoshita ◽  
Kenichi Koike ◽  
Hadija Hemed Mwamtemi ◽  
Susumu Ito ◽  
Shuichi Ishida ◽  
...  
Keyword(s):  
Mast Cell ◽  
Retinoic Acid ◽  
Mast Cells ◽  
Cord Blood ◽  
Cell Development ◽  
Negative Regulator ◽  
Human Mast Cell ◽  
Target Cells ◽  
Dependent Manner ◽  
Selective Agonist

We examined the effects of retinoids on the human mast cell development using a serum-deprived culture system. When 10-week cultured mast cells derived from CD34+ cord blood cells were used as target cells, both all-trans retinoic acid (ATRA) and 9-cis RA inhibited the progeny generation under stimulation with stem cell factor (SCF) in a dose-dependent manner (the number of progeny grown by SCF plus RA at 10−7 mol/L was one tenth of the value obtained by SCF alone). The early steps in mast cell development appear to be less sensitive to RA according to the single CD34+c-kit+ cord blood cell culture study. The optimal concentration of RAs also reduced the histamine concentration in the cultured mast cells (3.00 ± 0.47 pg per cell in SCF alone, 1.44 ± 0.18 pg per cell in SCF+ATRA, and 1.41 ± 0.10 pg per cell in SCF+9-cis RA). RT-PCR analyses showed the expression of RAR, RARβ, RXR, and RXRβ messenger ribonucleic acid (mRNA) in 10-week cultured mast cells. The addition of an RAR-selective agonist at 10−10 mol/L to 10−7 mol/L decreased the number of mast cells grown in SCF, whereas an RXR-selective agonist at up to 10−8 mol/L was inactive. Among RAR subtype selective retinoids used at 10−9 mol/L to 10−7 mol/L, only the RAR agonist was equivalent to ATRA at 10−7 mol/L in its ability to inhibit mast cell growth. Conversely, the addition of excess concentrations of a RAR antagonist profoundly counteracted the retinoid-mediated suppressive effects. These results suggest that RA inhibits SCF-dependent differentiation of human mast cell progenitors through a specific receptor.

scholarly journals Alisol B 23-Acetate Inhibits IgE/Ag-Mediated Mast Cell Activation and Allergic Reaction

2018 ◽  
Vol 19 (12) ◽  
pp. 4092 ◽  
Author(s):  
Chen Shao ◽  
Bingjie Fu ◽  
Ning Ji ◽  
Shunli Pan ◽  
Xiaoxia Zhao ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Allergic Reaction ◽  
Nuclear Factor Kappa B ◽  
Immunoglobulin E ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa

Alisol B 23-acetate (AB23A), a natural triterpenoid, has been reported to exert hepatoprotective and antitumor activities. Aiming to investigate the anti-inflammatory activity, this study examined the effect of AB23A on mast cells and allergic reaction. AB23A inhibited the degranulation of mast cells stimulated by immunoglobulin E/antigen (IgE/Ag), and also decreased the synthesis of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) in a concentration-dependent manner with no significant cytotoxicity in bone marrow-derived mast cells (BMMCs). AB23A inhibited spleen tyrosine kinase (Syk) and the downstream signaling molecules including phospholipase Cγ (PLCγ), serine-threonine protein kinase/inhibitor of nuclear factor kappa-B kinase/nuclear factor kappa-B (Akt/IKK/NF-κB), and mitogen-activated protein kinases/cytosolic phospholipase A2 (MAPK/cPLA2). Furthermore, AB23A blocked mobilization of Ca2+. Similar results were obtained in other mast cell lines Rat basophilic leukemia (RBL)-2H3 cells and a human mast cell line (HMC-1). In addition, AB23A attenuated allergic responses in an acute allergy animal model, passive cutaneous anaphylaxis (PCA). Taken together, this study suggests that AB23A inhibits the activation of mast cells and ameliorates allergic reaction, and may become a lead compound for the treatment of mast cell-mediated allergic diseases.

Development of both human connective tissue-type and mucosal-type mast cells in mice from hematopoietic stem cells with identical distribution pattern to human body

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 860-867 ◽  
Author(s):  
Naotomo Kambe ◽  
Hidefumi Hiramatsu ◽  
Mika Shimonaka ◽  
Hisanori Fujino ◽  
Ryuta Nishikomori ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mast Cell ◽  
Mast Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Development ◽  
Tissue Type ◽  
Human Mast Cell ◽  
Hematopoietic Stem ◽  
Nog Mice

Abstract The transplantation of primitive human cells into sublethally irradiated immune-deficient mice is the well-established in vivo system for the investigation of human hematopoietic stem cell function. Although mast cells are the progeny of hematopoietic stem cells, human mast cell development in mice that underwent human hematopoietic stem cell transplantation has not been reported. Here we report on human mast cell development after xenotransplantation of human hematopoietic stem cells into nonobese diabetic severe combined immunodeficient \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((\mathrm{NOD{/}SCID}){/}{\gamma}_{\mathrm{c}}^{null}\) \end{document} (NOG) mice with severe combined immunodeficiency and interleukin 2 (IL-2) receptor γ-chain allelic mutation. Supported by the murine environment, human mast cell clusters developed in mouse dermis, but they required more time than other forms of human cell reconstitution. In lung and gastric tract, mucosal-type mast cells containing tryptase but lacking chymase located on gastric mucosa and in alveoli, whereas connective tissue-type mast cells containing both tryptase and chymase located on gastric submucosa and around major airways, as in the human body. Mast cell development was also observed in lymph nodes, spleen, and peritoneal cavity but not in the peripheral blood. Xenotransplantation of human hematopoietic stem cells into NOG mice can be expected to result in a highly effective model for the investigation of human mast cell development and function in vivo.

scholarly journals Expression of Functional TrkA Receptor Tyrosine Kinase in the HMC-1 Human Mast Cell Line and in Human Mast Cells

Blood ◽  
1997 ◽  
Vol 90 (5) ◽  
pp. 1807-1820 ◽  
Author(s):  
See-Ying Tam ◽  
Mindy Tsai ◽  
Masao Yamaguchi ◽  
Koji Yano ◽  
Joseph H. Butterfield ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Tyrosine Kinase ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Human Mast Cell ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Human Mast Cells

Abstract Nerve growth factor (NGF ) can influence mast cell development and function in murine rodents by interacting with its receptors on mast cells. We now report the identification of mRNA transcripts of full-length tyrosine kinase-containing trkA, trkB, and trkC neurotrophin receptor genes in HMC-1 human mast cell leukemia cells. Although HMC-1 cells lacked p75 mRNA, they expressed transcripts for the exon-lacking splice variant of trkA (trkAI), truncated trkB (trkB.T1), and truncated trkC. By flow cytometry, HMC-1 cells exhibited expression of TrkA, TrkB, and TrkC receptor proteins containing full-length tyrosine kinase domains. NGF stimulation of HMC-1 cells induced tyrosine phosphorylation of TrkA protein, increased expression of the early response genes c-fos and NGF1-A, and activation of ERK-mitogen–activated protein (MAP) kinase, results which indicate that TrkA receptors in HMC-1 cells are fully functional. Highly purified populations of human lung mast cells expressed mRNAs for trkA, trkB and trkC, whereas preparations of human umbilical cord blood-derived mast cells expressed mRNAs for trkA and trkC, but not trkB. Moreover, preparations of human umbilical cord blood-derived immature mast cells not only expressed mRNA transcript and protein for TrkA, but exhibited significantly higher numbers of chymase-positive cells after the addition of NGF to their culture medium for 3 weeks. In addition, HMC-1 cells expressed mRNAs for NGF, brain-derived neurotrophic factor (BDNF ), and neurotrophin-3 (NT-3), the cognate ligands for TrkA, TrkB, and TrkC, whereas NGF and BDNF transcripts were detectable in human umbilical cord blood mast cell preparations. Taken together, our findings show that human mast cells express a functional TrkA receptor tyrosine kinase and indicate that NGF may be able to promote certain aspects of mast cell development and/or maturation in humans. Our studies also raise the possibility that human mast cells may represent a potential source for neurotrophins.

scholarly journals Suplatast Tosilate Inhibits Human Mast Cell Development from Cord Blood Progenitors

2005 ◽  
Vol 54 (2) ◽  
pp. 311-315
Author(s):  
Akihiro Fujisawa ◽  
Naotomo Kambe ◽  
Tatsutoshi Nakahata ◽  
Hiroshi Matsuda ◽  
Yoshiki Miyachi
Keyword(s):  
Mast Cell ◽  
Cord Blood ◽  
Cell Development ◽  
Human Mast Cell

scholarly journals Hypoxia modulates human mast cell adhesion to hyaluronic acid

2021 ◽  
Author(s):  
Joanna Pastwińska ◽  
Aurelia Walczak-Drzewiecka ◽  
Elżbieta Kozłowska ◽  
Enjuro Harunari ◽  
Marcin Ratajewski ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Mast Cell ◽  
Hyaluronic Acid ◽  
Cell Adhesion ◽  
Mast Cells ◽  
Immune Cell ◽  
Human Mast Cell ◽  
Dependent Manner ◽  
Cell Functions ◽  
Extracellular Matrix Components

AbstractHypoxia is an inherent factor in the inflammatory process and is important in the regulation of some immune cell functions, including the expression of mast cell pro- and anti-inflammatory mediators. Hypoxia also influences cell adhesion to the extracellular matrix (ECM). Hyaluronic acid is one of the major components of the ECM that is involved in inflammatory and tissue regeneration processes in which mast cells play a prominent role. This prompted us to investigate the effects of hypoxia on the expression of hyaluronic acid receptors in mast cells and mast cell adhesion to this ECM component. We found that human LAD2 mast cells spontaneously adhered to hyaluronic acid in a CD44-dependent manner and that reduced oxygen concentrations inhibited or even completely abolished this adhesion process. The mechanism of hypoxia downregulation of mast cell adhesion to hyaluronic acid did not involve a decrease in CD44 expression and hyaluronidase-mediated degradation of adhesion substrates but rather conformational changes in the avidity of CD44 to hyaluronic acid. Hypoxia-mediated regulation of mast cell adhesion to extracellular matrix components might be involved in the pathogenic accumulation of mast cells observed in the course of certain diseases including rheumatoid arthritis and cancer.

scholarly journals Differential expression of leukocyte immunoglobulin-like receptors on cord blood-derived human mast cell progenitors and mature mast cells

2007 ◽  
Vol 83 (2) ◽  
pp. 334-343 ◽  
Author(s):  
Nicodemus Tedla ◽  
Chyh-Woei Lee ◽  
Luis Borges ◽  
Carolyn L. Geczy ◽  
Jonathan P. Arm
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cord Blood ◽  
Differential Expression ◽  
Human Mast Cell

Mast cells release cytokines in response to mediators produced by virus-infected epithelial cellss

2007 ◽  
Vol 30 (4) ◽  
pp. 96
Author(s):  
Candy Tsang ◽  
A. D. Befus
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Epithelial Cells ◽  
Viral Infections ◽  
Allergic Diseases ◽  
Type I Interferons ◽  
Human Mast Cell ◽  
Type I ◽  
Dependent Manner ◽  
Tlr Agonists

Background: Mast cells have long been recognized for their involvement in allergic diseases. In the last decade, the importance of mast cells in innate responses against bacteria has been established, but little is known about their contribution in viral infections. Mast cells are abundant at mucosal surfaces such as the lungs in close proximity to the epithelium. In the lung, the epithelium is a primary target for viral infections. Mast cells are secondarily exposed to newly formed virions released from epithelial cells. Mast cells have toll-like receptors (TLRs) that detect various pathogen components. Our first hypothesis is that viral TLR agonists will induce mast cells to release cytokines thought to be involved in viral infections. Both the pro-inflammatory cytokine IL-6 and the chemokine IL-8 are produced during viral infections. TGF-β is an immunoregulatory cytokine that modulates the activity of various immune cells and could also play a role in viral infections. Methods: We used polyI:C, a synthetic double-stranded RNA (dsRNA), as a TLR3 agonist, loxoribine as a TLR7 agonist, and unmethylated CpG DNA as a TLR9 agonist. We treated mast cells from the cell line HMC-1 (Human Mast cell-1) for 0.5 – 24hr with the TLR agonists and performed dose response studies for all stimuli. Supernatants from treated mast cells were measured for IL-6, IL-8, and TGF-β by ELISA. Results: Cytokine release was highest at the 24hr time point. Mast cells released IL-6, IL-8, and TGF-β in response to the TLR3 agonist polyI:C in a dose-dependent manner, but not to the other viral TLR agonists. PolyI:C (10μg/mL) versus unstimulated controls significantly increased mast cell release of IL-6 (224.7±57.4 vs. 39.0±5.7, p≤0.001) and TGF-β (240.2±28.9 vs. 116.1±16.7, p≤0.05). PolyI:C induced release of IL-8 from mast cells was increased but not significant. Viral exposure also induces epithelial cells to produce type I interferons, IFNα and β. These interferons have potent antiviral activity, but also have effects on mast cells, decreasing mast cell adhesion to extracellular matrix and reducing co-stimulatory activity on T cells. Our second hypothesis is that IFNα and β will induce mast cells to release cytokines similar to stimulation with polyI:C. Our preliminary data showed that IFNα, IFNβ , and IFNα and β in combination induced a low level of IL-8 and TGF-β release from mast cells, but had no effect on IL-6 release. Conclusion: HMC-1 responds to dsRNA, a TLR3 agonist produced in epithelial cells during viral replication, by releasing IL-6 and TGF-β. HMC-1 also responds to IFNα and β by releasing IL-8 and TGF-β, indicating that human mast cells respond to epithelial mediators produced during viral infections. Our results show that mast cells contribute to the innate response against viruses by responding to mediators released by virus-infected epithelial cells.

MMP dependence of fibroblast contraction and collagen production induced by human mast cell activation in a three-dimensional collagen lattice

2009 ◽  
Vol 296 (2) ◽  
pp. L236-L247 ◽  
Author(s):  
Alexander Margulis ◽  
Karl H. Nocka ◽  
Nancy L. Wood ◽  
Stanley F. Wolf ◽  
Samuel J. Goldman ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Three Dimensional ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Dependent Manner ◽  
Proteolytic Activation ◽  
Collagen Production ◽  
Collagen Lattice

Mast cell-fibroblast interactions may contribute to fibrosis in asthma and other disease states. Fibroblast contraction is known to be stimulated by coculture with the human mast cell line, HMC-1, or by mast cell-derived agents. Matrix metalloproteinases (MMPs) can also mediate contraction, but the MMP-dependence of mast cell-induced fibroblast contractility is not established, and the consequences of mast cell activation within the coculture system have not been fully explored. We demonstrate that activation of primary human mast cells (pHMC) with IgE receptor cross-linking, or activation of HMC-1 with C5a, enhanced contractility of human lung fibroblasts in a three-dimensional collagen lattice system. This enhanced contractility was inhibited by the pan-MMP antagonist, batimastat, and was transferrable in the conditioned medium of activated mast cells. Exogenously added MMPs promoted gel contraction by mediating the proteolytic activation of latent transforming growth factor-β (TGF-β). Consistent with this, fibroblast contraction induced by mast cell activation was enhanced by addition of excess latent TGF-β to the cultures. Batimastat inhibited this response, suggesting that MMPs capable of activating latent TGF-β were released following mast cell activation in coculture with fibroblasts. Collagen production was also stimulated by activated mast cells in an MMP-dependent manner. MMP-2 and MMP-3 content of the gels increased in the presence of activated mast cells, and inhibition of these enzymes blocked the contractile response. These findings demonstrate the MMP dependence of mast cell-induced fibroblast contraction and collagen production.

scholarly journals GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1802
Author(s):  
Nayoung Kim ◽  
Mi Yeon Kim ◽  
Woo Seon Choi ◽  
Eunbi Yi ◽  
Hyo Jung Lee ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Negative Regulator ◽  
Target Cells ◽  
Dependent Manner ◽  
Cell Functions ◽  
Cell Based Therapy ◽  
Activating Receptors ◽  
Gsk 3Β

Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

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