title: Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease.
abstract: Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Here we show that recombinant human PTX-2 (rhPTX-2) retards progression of chronic kidney disease inCol4a3mutant mice with Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously delivered rhPTX-2 was detected in macrophages but also in tubular epithelial cells, where it counteracted macrophage activation and was cytoprotective for the epithelium. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun along with its activator protein-1 (AP-1) binding partners as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun and AP-1 activity, and reduces expression of AP-1-dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting.
authors.affiliation: Division of Nephrology, Departments of Medicine and Pathology, and.|Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.|Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakagawa
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Barron
authors.affiliation: Division of Nephrology, Departments of Medicine and Pathology, and.|Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.|Research and Development, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Gomez
authors.affiliation: Division of Nephrology, Departments of Medicine and Pathology, and.|Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.|Research and Development, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Bryce G
authors.initials: BG
authors.lastname: Johnson
authors.affiliation: Division of Nephrology, Departments of Medicine and Pathology, and.|Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.|Research and Development, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Allie M
authors.initials: AM
authors.lastname: Roach
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Sei
authors.initials: S
authors.lastname: Kameoka
authors.affiliation: Promedior Inc., Lexington, Massachusetts, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Jack
authors.affiliation: Promedior Inc., Lexington, Massachusetts, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Lupher
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.|Computational Medicine Core.|Divsion of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.affiliation: Division of Nephrology, Departments of Medicine and Pathology, and.|Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.|Research and Development, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000494:pharmacology*; D002478:Cells, Cultured; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008262:Macrophage Activation; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009000:Monocytes; D009394:Nephritis, Hereditary / Q000473:pathology / Q000628:therapy*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D009419:Nerve Tissue Proteins; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D000099153:Pentraxins