title: Clemastine causes immune suppression through inhibition of extracellular signal-regulated kinase-dependent proinflammatory cytokines.
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.
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. pal.johansen@usz.ch
authors.forename: Pål
authors.initials: P
authors.lastname: Johansen
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.forename: Antonia
authors.initials: A
authors.lastname: Bünter
authors.forename: Ying
authors.initials: Y
authors.lastname: Waeckerle-Men
authors.forename: Antonia
authors.initials: A
authors.lastname: Fettelschoss
authors.forename: Bernhard
authors.initials: B
authors.lastname: Odermatt
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kündig
mesh_terms: D000818:Animals; D002974:Clemastine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects* / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy / Q000009:adverse effects; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D006634:Histamine H1 Antagonists; D002974:Clemastine; D048049:Extracellular Signal-Regulated MAP Kinases