title: S100A8 induces IL-10 and protects against acute lung injury.
abstract: S100A8 is considered proinflammatory by activating TLR4 and/or the receptor for advanced glycation end products. The aim was to investigate inflammatory effects of S100A8 in murine lung. S100A8 was administered to BALB/c mice by nasal inhalation and genes induced over a time-course assessed. LPS was introduced intranasally either alone or 2 h after pretreatment of mice with intranasal application of S100A8 or dexamethasone. A Cys(42)-Ala(42) mutant S100A8 mutant was used to assess whether S100A8's effects were via pathways that were dependent on reactive oxygen species. S100A8 induced IL-10 mRNA, and expression was apparent only in airway epithelial cells. Importantly, it suppressed acute lung injury provoked by LPS inhalation by suppressing mast-cell activation and induction of mediators orchestrating leukocyte recruitment, possibly by reducing NF-κB activation via an IκBα/Akt pathway and by downmodulating pathways generating oxidative stress. The Cys(42)-Ala(42) S100A8 mutant did not induce IL-10 and was less immunosuppressive, indicating modulation by scavenging oxidants. S100A8 inhibition of LPS-mediated injury was as potent, and outcomes were remarkably similar to immunosuppression by dexamethasone. We challenge the notion that S100A8 is an agonist for TLR4 or the receptor for advanced glycation end products. S100A8 induced IL-10 in vivo and initiates a feedback loop that attenuates acute lung injury.
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hiroshima
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hsu
authors.forename: Nicodemus
authors.initials: N
authors.lastname: Tedla
authors.forename: Yuen Ming
authors.initials: YM
authors.lastname: Chung
authors.forename: Sharron
authors.initials: S
authors.lastname: Chow
authors.forename: Cristan
authors.initials: C
authors.lastname: Herbert
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Geczy
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000281:Administration, Intranasal; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D015153:Blotting, Western; D040501:Calgranulin A / Q000008:administration & dosage* / Q000235:genetics; D016000:Cluster Analysis; D003907:Dexamethasone / Q000008:administration & dosage; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D050505:Mutant Proteins / Q000008:administration & dosage / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D040501:Calgranulin A; D008070:Lipopolysaccharides; D050505:Mutant Proteins; D016753:Interleukin-10; D003907:Dexamethasone