title: Pim1 kinase activity preserves airway epithelial integrity upon house dust mite exposure.
abstract: Most patients with allergic asthma are sensitized to house dust mite (HDM). The allergenicity of HDM largely depends on disruption of the integrity and proinflammatory activation of the airway epithelium. In this study, we hypothesized that Pim1 kinase activity attenuates HDM-induced asthma by preserving airway epithelial integrity. The effects of Pim1 kinase activity on barrier function and release of the proinflammatory mediators IL-1α and CCL20 were studied in vitro in 16HBE and primary bronchial epithelial cells (PBECs). Pim1-proficient and -deficient mice were exposed to a HDM-driven model of allergic asthma, and airway hyperresponsiveness (AHR) was measured upon methacholine challenge. Airway inflammation and proinflammatory mediators in lung tissue and BAL fluid were determined. We observed that inhibition of Pim1 kinase prolongs the HDM-induced loss of barrier function in 16HBE cells and sensitizes PBECs to HDM-induced barrier dysfunction. Additionally, inhibition of Pim1 kinase increased the HDM-induced proinflammatory activity of 16HBE cells as measured by IL-1α secretion. In line herewith, HDM exposure induced an enhanced production of the proinflammatory chemokines CCL17 and CCL20 in Pim1-deficient mice compared with wild-type controls. While we observed a marked increase in eosinophilic and neutrophilic granulocytes as well as mucus cell metaplasia and AHR to methacholine in mice exposed to HDM, these parameters were independent of Pim1 kinase activity. In contrast, levels of the Th2-cytokines IL-5 and IL-10 were significantly augmented in HDM-treated Pim1-deficient mice. Taken together, our study shows that Pim1 kinase activity maintains airway epithelial integrity and protects against HDM-induced proinflammatory activation of the airway epithelium.
authors.affiliation: Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands m.de.vries04@umcg.nl.
authors.forename: M
authors.initials: M
authors.lastname: de Vries
authors.affiliation: Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Hesse
authors.affiliation: Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: M R
authors.initials: MR
authors.lastname: Jonker
authors.affiliation: Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: A J M
authors.initials: AJ
authors.lastname: van Oosterhout
authors.affiliation: Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: I H
authors.initials: IH
authors.lastname: Heijink
authors.affiliation: Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Nawijn
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001980:Bronchi / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology* / Q000469:parasitology* / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000469:parasitology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D011014:Pneumonia / Q000473:pathology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D039981:Pyroglyphidae / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000201:enzymology / Q000469:parasitology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology; D055815:Young Adult
chemical_list: D018925:Chemokines; D018836:Inflammation Mediators; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1
keywords: Th2-cytokines; allergen; eosinophils; epithelial barrier function; innate immune response