title: Interactions between leukotriene C4 and interleukin 13 signaling pathways in a mouse model of airway disease.
abstract: BACKGROUND
  During an asthmatic episode, leukotriene C4 (LTC4) and interleukin 13 (IL-13) are released into the airways and are thought to be central mediators of the asthmatic response. However, little is known about how these molecules interact or affect each other's signaling pathway.
  
  
  OBJECTIVE
  To determine if the LTC4 and IL-13 signaling pathways interact with each other's pathways.
  
  
  METHODS
  We examined airway responsiveness, cysteinyl LTs (Cys-LTs), and Cys-LT and IL-13 receptor transcript levels in wild-type mice and in mice that were deficient in gamma-glutamyl leukotrienase (an enzyme that converts LTC4 to LTD4), STAT6 (signal transducer and activator of transcription 6 [a critical molecule in IL-13 signaling]), and IL-4Ralpha (a subunit of the IL-13 receptor).
  
  
  RESULTS
  Wild-type (C57BL/129SvEv) and gamma-glutamyl leukotrienase-deficient mice showed increased airway responsiveness after intranasal instillation of IL-13; similar results were observed after intranasal instillation of IL-13 or LTC4 in a second wild-type strain (BALB/c). Interleukin 13 treatment reduced levels of Cys-LTs in bronchoalveolar lavage fluid. This change was unaccompanied by changes in other arachidonic acid metabolites or in RNA transcript levels of enzymes associated with Cys-LT synthesis. Interleukin 13 treatment also increased transcript levels of the Cys-LT 1 and Cys-LT 2 receptors, while LTC4 increased transcript levels of the alpha1 chain of the IL-13 receptor. Furthermore, IL-4Ralpha-deficient mice had increased airway responsiveness to LTC4 but not to IL-13, whereas STAT6-deficient mice failed to respond to either agonist.
  
  
  CONCLUSIONS
  These findings indicate that LTC4 and IL-13 are dependent on or signal through STAT6 to increase airway responsiveness and that both agonists regulate expression of each other's receptors.
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Chavez
authors.forename: Hays W J
authors.initials: HW
authors.lastname: Young
authors.forename: David B
authors.initials: DB
authors.lastname: Corry
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lieberman
mesh_terms: D000403:Airway Resistance / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004150:Dipeptidases / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism* / Q000494:pharmacology; D053661:Interleukin-13 Receptor alpha1 Subunit; D017997:Leukotriene C4 / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction
chemical_list: C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D008565:Membrane Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D018077:Receptors, Leukotriene; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D017997:Leukotriene C4; D004150:Dipeptidases; C405510:gamma-glutamyl leukotrienase; C083169:leukotriene D4 receptor