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Clemastine causes immune suppression through inhibition of extracellular signal-regulated kinase-dependent proinflammatory cytokines


Johansen, P; Weiss, A; Bünter, A; Waeckerle-Men, Y; Fettelschoss, A; Odermatt, B; Kündig, T M (2011). Clemastine causes immune suppression through inhibition of extracellular signal-regulated kinase-dependent proinflammatory cytokines. Journal of Allergy and Clinical Immunology, 128(6):1286-1294.

Abstract

BACKGROUND:

Antihistamines are considered safe and used worldwide against allergy, pruritus, nausea, and cough and as sleeping aids. Nonetheless, a growing number of reports suggest that antihistamines also have immunoregulatory functions.
OBJECTIVE:

We examined the extent and by what potential mechanisms histamine-1-receptor (H1R) antagonists exert immune suppressive effects.
METHODS:

Immune suppression by antihistamines and immunosuppressants was tested in mice infected with Listeria monocytogenes. Potential modes of action were studied in vitro by using murine and human cells. We also tested whether injection of clemastine in healthy volunteers affected the activation of peripheral macrophages and monocytes. Finally, therapeutic application of clemastine-mediated immune suppression was tested in a murine model of sepsis.
RESULTS:

Clemastine and desloratadine strongly reduced innate responses to Listeria monocytogenes in mice as did dexamethasone. The immune suppression was MyD88 independent and characterized by inhibition of the mitogen-activated protein kinase-extracellular signal-regulated kinase signaling pathway, leading to overall impaired innate immunity with reduced TNF-α and IL-6 production. Surprisingly, the observed effects were H1R independent as demonstrated in H1R-deficient mice. Moreover, in a double-blind placebo-controlled clinical trial, 1 intravenous administration of clemastine reduced the TNF-α secretion potential of peripheral blood macrophages and monocytes. This inhibition could be exploited to treat sepsis in mice.
CONCLUSIONS:

The safety profile of antihistamines may need to be revisited. However, antihistamine-mediated immune suppression may also be exploited and find applications in the treatment of inflammatory diseases.

Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

BACKGROUND:

Antihistamines are considered safe and used worldwide against allergy, pruritus, nausea, and cough and as sleeping aids. Nonetheless, a growing number of reports suggest that antihistamines also have immunoregulatory functions.
OBJECTIVE:

We examined the extent and by what potential mechanisms histamine-1-receptor (H1R) antagonists exert immune suppressive effects.
METHODS:

Immune suppression by antihistamines and immunosuppressants was tested in mice infected with Listeria monocytogenes. Potential modes of action were studied in vitro by using murine and human cells. We also tested whether injection of clemastine in healthy volunteers affected the activation of peripheral macrophages and monocytes. Finally, therapeutic application of clemastine-mediated immune suppression was tested in a murine model of sepsis.
RESULTS:

Clemastine and desloratadine strongly reduced innate responses to Listeria monocytogenes in mice as did dexamethasone. The immune suppression was MyD88 independent and characterized by inhibition of the mitogen-activated protein kinase-extracellular signal-regulated kinase signaling pathway, leading to overall impaired innate immunity with reduced TNF-α and IL-6 production. Surprisingly, the observed effects were H1R independent as demonstrated in H1R-deficient mice. Moreover, in a double-blind placebo-controlled clinical trial, 1 intravenous administration of clemastine reduced the TNF-α secretion potential of peripheral blood macrophages and monocytes. This inhibition could be exploited to treat sepsis in mice.
CONCLUSIONS:

The safety profile of antihistamines may need to be revisited. However, antihistamine-mediated immune suppression may also be exploited and find applications in the treatment of inflammatory diseases.

Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

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9 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:31 July 2011
Deposited On:12 Feb 2012 10:04
Last Modified:05 Apr 2016 15:34
Publisher:Elsevier
ISSN:0091-6749 (P) 1097-6825 (E)
Publisher DOI:https://doi.org/10.1016/j.jaci.2011.06.023
PubMed ID:21807405
Permanent URL: https://doi.org/10.5167/uzh-58475

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