title: Deficiency of FHL2 attenuates airway inflammation in mice and genetic variation associates with human bronchial hyper-responsiveness.
abstract: BACKGROUND
  Asthma is an inflammatory disease that involves airway hyper-responsiveness and mucus hypersecretion. The LIM-only protein FHL2 is a crucial modulator of multiple signal transduction pathways and functions as a scaffold in specific protein-protein interactions.
  
  
  OBJECTIVE
  We sought to investigate the role of FHL2 in airway inflammation.
  
  
  METHODS
  Allergic airway inflammation was induced in WT and FHL2-knock out (FHL2-KO) mice with ovalbumin (OVA). Lung tissue, bronchoalveolar lavage fluid (BALF) and draining lymph node cells were analysed for inflammation. FHL2 loss and gain of function studies were performed in lung epithelial cells.
  
  
  RESULTS
  FHL2-deficient mice challenged with OVA show significantly reduced airway inflammation as evidenced by reduced infiltration of inflammatory cells including eosinophils, dendritic cells, B cells and T cells. Furthermore, mucus production was decreased in FHL2-KO mice. In BALF, the levels of IL-5, IL-13, eotaxin-1 and eotaxin-2 were significantly lower in FHL2-KO mice. In addition, draining lymph node cells from FHL2-KO mice show reduced levels of IL-5 and IL-13. Consistent with this, OVA-specific serum IgG and IgE levels were reduced in FHL2-KO mice. We also found that phosphorylation of ERK1/2 is markedly attenuated in FHL2-KO lung. Knock-down of FHL2 in human lung epithelial cells resulted in a striking decrease in ERK1/2 phosphorylation and mRNA levels of inflammatory cytokines and MUC5AC, whereas FHL2 overexpression exhibited opposite effects. Finally, the SNP rs4851765 shows an association with the severity of bronchial hyper-responsiveness.
  
  
  CONCLUSIONS
  These results highlight functional involvement of FHL2 in airway inflammation and identify FHL2 as a novel gene associated with asthma severity in human.
authors.affiliation: Deartment of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Kurakula
authors.affiliation: Deartment of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Vos
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Logiantara
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: J J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Nieuwenhuis
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: G H
authors.initials: GH
authors.lastname: Koppelman
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: C A
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: The University of British Columbia James Hogg Research Laboratory, St Paul's Hospital, Vancouver, Canada.|Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: D D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: Department of Molecular Medicine, Laval University, Quebec City, Canada.|Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Laval University, Quebec City, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: Genetics, Rosetta Inpharmatics, Merck, Seattle, WA, USA.|Merck Research Laboratories, Boston, MA, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Nickle
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: L S
authors.initials: LS
authors.lastname: van Rijt
authors.affiliation: Deartment of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C J M
authors.initials: CJ
authors.lastname: de Vries
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011014:Pneumonia / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012130:Respiratory Hypersensitivity / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C105987:FHL2 protein, human; C491382:Fhl2 protein, mouse; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors
keywords: FHL2; airway inflammation; bronchial hyper-responsiveness; epithelial cells; pERK1/2