title: IL-1beta induces murine airway 5-HT2A receptor hyperresponsiveness via a non-transcriptional MAPK-dependent mechanism.
abstract: BACKGROUND
  Interleukin 1 beta (IL-1beta) is found in bronchoalveolar lavage fluids from asthmatic patients and plays an important role in normal immunoregulatory processes but also in pathophysiological inflammatory responses. The present study was designed to investigate if IL-1beta could be involved in the development of airway hyperresponsiveness and if transcriptional mechanisms, epithelium contractile factors and mitogen-activated protein kinase (MAPK) pathways are involved in IL-1beta effect.
  
  
  METHODS
  The effect of IL-1beta on 5-hydroxytryptamine (5-HT) induced bronchoconstriction was evaluated in an in-vitro model for assessment of long-term effects of inflammatory mediators on the airway smooth muscle. Murine tracheal segments were cultured up to 8 days in the absence or presence of IL-1beta with subsequent evaluation in a myograph system, along with mRNA quantification, focusing on the role of the epithelium, acetylcholine release, transcriptional mechanisms and MAPK activity.
  
  
  RESULTS
  During control conditions, 5-HT induced a relatively weak contraction. Presence of IL-1beta increased this response in a time- and concentration-dependent way. The increased concentration-effect curves could be shifted rightwards in a parallel manner by ketanserin, a selective 5-HT2A receptor antagonist, indicating that the responses are mediated by 5-HT2A receptors. The mRNA levels of 5-HT2A receptors were not changed as a consequence of the IL-1beta treatment and actinomycin D, a general transcriptional inhibitor, failed to affect the contractile response, suggesting a non-transcriptional mechanism behind this phenomenon. Neither the removal of the epithelium nor the addition of atropine affected the IL-1beta induced enhancement of 5-HT2A receptor-mediated contractile response. Application of inhibitors for c-Jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase 1 and 2 (ERK1/2) showed that the signaling pathways for JNK and ERK1/2 dominated only in cultured segments (control) whereas JNK and p38 dominated in segments treated with IL-1beta.
  
  
  CONCLUSIONS
  IL-1beta induces murine airway hyperresponsiveness, via a non-transcriptional up-regulation of 5-HT2A receptor-mediated contractile response. The increase of 5-HT contraction is unrelated to epithelial and cholinergic factors, but is dependent on IL-1beta-induced changes of MAPK pathways. The fact that IL-1beta can alter airway responses to contractile agents such as 5-HT, via alteration of the intracellular MAPK signal transduction pathways, might provide a new concept for future treatment of asthma.
authors.affiliation: Laboratory of Clinical and Experimental Allergy Research, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden. yaping.zhang@med.lu.se
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lars-Olaf
authors.initials: LO
authors.lastname: Cardell
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin; D014132:Trachea / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin