title: Peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1) regulates pulmonary effects of endotoxin and tumor necrosis factor-α in mice.
abstract: Peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1) modulates phospho-signaling by catalyzing rotation of the bond between a phosphorylated serine or threonine before proline in proteins. As depletion of PIN1 increased inflammatory protein expression in cultured endothelial cells treated with bacterial endotoxin (lipopolysaccharide, LPS) and interferon-γ, we hypothesized that PIN1 knockout would increase sensitivity to LPS-induced lung inflammation in mice. Mortality due to a high dose of LPS (30mg/kg) was greater in knockout than wildtype mice. Lung myeloperoxidase activity, reflecting neutrophils, was increased to a 35% higher level in PIN1 knockout mouse lung, as compared with wildtype, after treatment with a sublethal dose of 3mgLPS/kg, ip. Unexpectedly, plasma tumor necrosis factor-α (TNF) was approximately 50% less than in wildtype mice. Knockout mice, however, were more sensitive than wildtype to TNF-induced neutrophil accumulation. The neutrophil adhesion molecule, E-selectin, was also elevated in lungs of knockout mice treated with TNF, suggesting that PIN1 depletion increases endothelial sensitivity to TNF. Indeed, TNF induced more reactive oxygen species in cultured endothelial cells depleted of PIN1 with short hairpin RNA than in control cells. Collectively, the results indicate that while PIN1 normally facilitates TNF production in LPS-treated mice, it suppresses pulmonary and endothelial reactions to the cytokine. Tissue or cell-specific effects of PIN1 may affect the overall inflammatory response to LPS and other stimuli.
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: liu.tongzheng@mayo.edu.
authors.forename: Tongzheng
authors.initials: T
authors.lastname: Liu
authors.affiliation: College of Pharmacy, The University of Findlay, Findlay, OH 45840, USA. Electronic address: schneiderr@findlay.edu.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Schneider
authors.affiliation: Division of Pharmacology, The Ohio State University College of Pharmacy and The Dorothy M. Davis Heart and Lung Research Institute, Columbus, OH 43210, USA. Electronic address: lee.5064@osu.edu.
authors.forename: Nam Y
authors.initials: NY
authors.lastname: Lee
authors.affiliation: Division of Pharmacology, The Ohio State University College of Pharmacy and The Dorothy M. Davis Heart and Lung Research Institute, Columbus, OH 43210, USA. Electronic address: hoyt.27@osu.edu.
authors.forename: Dale G
authors.initials: DG
authors.lastname: Hoyt
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000172:deficiency / Q000235:genetics*; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019040:E-Selectin; D008070:Lipopolysaccharides; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse
keywords: Endothelial cells; Endotoxin; Lung; PIN1; TNF