title: SHP-1 as a critical regulator of Mycoplasma pneumoniae-induced inflammation in human asthmatic airway epithelial cells.
abstract: Asthma is a chronic inflammatory disease in which airway epithelial cells are the first line of defense against exposure of the airway to infectious agents. Src homology protein (SHP)-1, a protein tyrosine phosphatase, is a negative regulator of signaling pathways that are critical to the development of asthma and host defense. We hypothesize that SHP-1 function is defective in asthma, contributing to the increased inflammatory response induced by Mycoplasma pneumoniae, a pathogen known to exacerbate asthma. M. pneumoniae significantly activated SHP-1 in airway epithelial cells collected from nonasthmatic subjects by bronchoscopy with airway brushing but not in cells from asthmatic subjects. In asthmatic airway epithelial cells, M. pneumoniae induced significant PI3K/Akt phosphorylation, NF-κB activation, and IL-8 production compared with nonasthmatic cells, which were reversed by SHP-1 overexpression. Conversely, SHP-1 knockdown significantly increased IL-8 production and PI3K/Akt and NF-κB activation in the setting of M. pneumoniae infection in nonasthmatic cells, but it did not exacerbate these three parameters already activated in asthmatic cells. Thus, SHP-1 plays a critical role in abrogating M. pneumoniae-induced IL-8 production in nonasthmatic airway epithelial cells through inhibition of PI3K/Akt and NF-κB activity, but it is defective in asthma, resulting in an enhanced inflammatory response to infection.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. ying.wang5@duke.edu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.forename: Tony D
authors.initials: TD
authors.lastname: Church
authors.forename: Njira L
authors.initials: NL
authors.lastname: Lugogo
authors.forename: Loretta G
authors.initials: LG
authors.lastname: Que
authors.forename: Dave
authors.initials: D
authors.lastname: Francisco
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ingram
authors.forename: Molly
authors.initials: M
authors.lastname: Huggins
authors.forename: Denise M
authors.initials: DM
authors.lastname: Beaver
authors.forename: Jo Rae
authors.initials: JR
authors.lastname: Wright
authors.forename: Monica
authors.initials: M
authors.lastname: Kraft
mesh_terms: D000328:Adult; D001249:Asthma / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured / Q000201:enzymology / Q000276:immunology; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009177:Mycoplasma pneumoniae / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D016209:Interleukin-8; D016328:NF-kappa B; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6