Chemical mediator and cytokine release from mast cells and effects of anti-allergic drugs.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease which presents a grave prognosis for diagnosed patients. Nintedanib (a triple tyrosine kinase inhibitor) and pirfenidone (unclear mechanism of action) are the only approved therapies for IPF, but have limited efficacy. The pathogenic mechanisms of this disease are not fully elucidated; however, a role for mast cells (MCs) has been postulated.ObjectivesThe aim of this work was to investigate a role for MCs in IPF and to understand whether nintedanib or pirfenidone could impact MC function.Methods and resultsMCs were significantly elevated in human IPF lung and negatively correlated with baseline lung function (FVC). Importantly, MCs were positively associated with the number of fibroblast foci, which has been linked to increased mortality. Furthermore, MCs were increased in the region immediately surrounding the fibroblast foci, and co-culture studies confirmed a role for MC–fibroblast crosstalk in fibrosis. Nintedanib but not pirfenidone inhibited recombinant stem cell factor (SCF)–induced MC survival. Further evaluation of nintedanib determined that it also inhibited human fibroblast-mediated MC survival. This was likely via a direct effect on ckit (SCF receptor) since nintedanib blocked SCF-stimulated ckit phosphorylation, as well as downstream effects on MC proliferation and cytokine release. In addition, nintedanib ablated the increase in lung MCs and impacted high tissue density frequency (HDFm) in a rat bleomycin model of lung fibrosis.ConclusionNintedanib inhibits MC survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.

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Comparative effects of loratadine and desloratadine on cytokine release and adhesion molecule expression by human leukemic mast cells (HMC-1)

Journal of Allergy and Clinical Immunology ◽

10.1016/s0091-6749(02)81896-6 ◽

2002 ◽

Vol 109 (1) ◽

pp. S250-S250

Author(s):

Magda Babina ◽

Undine Lippert ◽

Beate M Henz

Keyword(s):

Mast Cells ◽

Adhesion Molecule ◽

Adhesion Molecule Expression ◽

Cytokine Release

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Borrelia burgdorferiSpirochetes Induce Mast Cell Activation and Cytokine Release

Infection and Immunity ◽

10.1128/iai.67.3.1107-1115.1999 ◽

1999 ◽

Vol 67 (3) ◽

pp. 1107-1115 ◽

Cited By ~ 22

Author(s):

Jeffrey Talkington ◽

Steven P. Nickell

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Cell Types ◽

Host Cells ◽

Mast Cell Activation ◽

Cytokine Release ◽

Necrosis Factor Alpha ◽

Tnf Α

ABSTRACT The Lyme disease spirochete, Borrelia burgdorferi, is introduced into human hosts via tick bites. Among the cell types present in the skin which may initially contact spirochetes are mast cells. Since spirochetes are known to activate a variety of cell types in vitro, we tested whether B. burgdorferi spirochetes could activate mast cells. We report here that freshly isolated rat peritoneal mast cells or mouse MC/9 mast cells cultured in vitro with live or freeze-thawed B. burgdorferi spirochetes undergo low but detectable degranulation, as measured by [5-3H] hydroxytryptamine release, and they synthesize and secrete the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). In contrast to findings in previous studies, where B. burgdorferi-associated activity was shown to be dependent upon protein lipidation, mast cell TNF-α release was not induced by either lipidated or unlipidated recombinant OspA. This activity was additionally shown to be protease sensitive and surface expressed. Finally, comparisons of TNF-α-inducing activity in known low-, intermediate-, and high-passage B. burgdorferi B31 isolates demonstrated passage-dependent loss of activity, indicating that the activity is probably plasmid encoded. These findings document the presence in low-passage B. burgdorferi spirochetes of a novel lipidation-independent activity capable of inducing cytokine release from host cells.

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Influences of Everninomicin, Vancomycin and Teicoplanin on Chemical Mediator Release From Rat Peritoneal Mast Cells

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)30564-5 ◽

2000 ◽

Vol 83 (4) ◽

pp. 300-305

Author(s):

Yukio Sugimoto ◽

Yoshinori Iba ◽

Keiko Utsugi ◽

Chiaki Kamei

Keyword(s):

Mast Cells ◽

Mediator Release ◽

Chemical Mediator ◽

Peritoneal Mast Cells ◽

Rat Peritoneal Mast Cells

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Lymphotoxin-β Receptor Activation by Activated T Cells Induces Cytokine Release from Mouse Bone Marrow-Derived Mast Cells

The Journal of Immunology ◽

10.4049/jimmunol.172.12.7459 ◽

2004 ◽

Vol 172 (12) ◽

pp. 7459-7465 ◽

Cited By ~ 51

Author(s):

Peter Stopfer ◽

Daniela N. Männel ◽

Thomas Hehlgans

Keyword(s):

Bone Marrow ◽

T Cells ◽

Mast Cells ◽

Receptor Activation ◽

Mouse Bone Marrow ◽

Cytokine Release ◽

Activated T Cells ◽

Β Receptor

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Wnt-3a Induces Cytokine Release in Human Mast Cells

Cells ◽

10.3390/cells8111372 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1372 ◽

Cited By ~ 2

Author(s):

Julia Tebroke ◽

Joris E. Lieverse ◽

Jesper Säfholm ◽

Gunnar Schulte ◽

Gunnar Nilsson ◽

...

Keyword(s):

Mast Cells ◽

Wnt Signaling ◽

Immune Cells ◽

Human Mast Cell ◽

Cytokine Release ◽

Human Mast Cells ◽

Cellular Expression ◽

Airway Diseases ◽

Allergies And Asthma

Mast cells are well known for their detrimental effects in allergies and asthma, and Wnt signaling has recently been implicated in asthma and other airway diseases. However, it is not known if or how Wnts affect human mast cells. Since Wnt expression is elevated in individuals with asthma and is linked to a Th2 profile, we hypothesized that mast cells could be affected by Wnts in the context of asthma. We therefore sought to investigate the role of Wnt signaling in human mast cell development and activation. We first examined the expression of the 10 main Wnt receptors, Frizzled 1–10 (FZD1–10), and found expression of several FZDs in human mast cells. Treatment with purified recombinant Wnt-3a or Wnt-5a did not affect the proliferation or maturation of CD34+ progenitors into mast cells, as indicated by cellular expression of CD117 and FcεRI, activation by FcεRI crosslinking, and histamine and tryptase release. Furthermore, Wnt treatment did not change the phenotype from MCT to MCTC, since MrgX2 expression, compound 48/80-mediated activation, and carboxypeptidase A3 content were not affected. However, Wnt-3a activated WNT/β-catenin signaling in mature human mast cells, as revealed by stabilization of β-catenin, upregulation of IL-8 and CCL8 mRNA expression, and release of IL-8 protein. Thus, our data suggest that Wnt-3a activation of mast cells could contribute to the recruitment of immune cells in conditions associated with increased Wnt-3a expression, such as asthma.

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