title: Mucosal toll-like receptor 3-dependent synthesis of complement factor B and systemic complement activation in inflammatory bowel disease.
abstract: BACKGROUND
  Recent studies link Toll-like receptor 3 (TLR3) to the pathogenesis of inflammatory bowel disease (IBD). Screening TLR3-agonist response in an intestinal epithelial cell line, we found complement factor B mRNA (CFB) potently upregulated and went on to further study localization of complement factor B synthesis and systemic activation of complement in ulcerative colitis and Crohn's disease.
  
  
  METHODS
  In a transcriptome analysis of poly (I:C) stimulated HT-29 cells, we found CFB highly upregulated downstream of TLR3. We sought to confirm CFB upregulation in a microarray gene expression analysis on colonic biopsies from an IBD population (n = 133). Immunohistochemical staining and in situ hybridization were done to identify cellular sources of factor B and CFB. Systemic complement activation was assessed in plasma (n = 18) using neoepitope-based enzyme linked immunosorbent assay.
  
  
  RESULTS
  CFB mRNA and protein were abundantly expressed in the colonic epithelial cell line, and synthesis enhanced by the poly (I:C) TLR3 ligand. In inflamed versus normal colonic mucosa of ulcerative colitis and Crohn's disease, CFB mRNA was the most significantly overexpressed gene and the mRNA abundance ratio was among the 50 highest. Epithelial cells were the dominating site of factor B expression. Systemic complement activation was significantly higher in active than in nonactive IBD.
  
  
  CONCLUSIONS
  This study is the first to link TLR3 to activation of the alternative complement pathway. Complement factor B is potently upregulated locally in IBD in addition to having a possible central role in systemic complement activation. This suggests a prominent role for complement in IBD pathogenesis.
authors.affiliation: *Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway; †Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; ‡Department of Gastroenterology and Hepatology, St. Olav's University Hospital, Trondheim, Norway; §Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway; ‖Department of Pathology and Medical Genetics, St. Olav's University Hospital, Trondheim, Norway; ¶Research Laboratory, Department of Laboratory Medicine, Nordland Hospital, Bodø, Norway; **Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen IRC, University of Oslo, Oslo, Norway; and ††Department of Infectious Diseases, St. Olav's University Hospital, Trondheim, Norway.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Ostvik
authors.forename: Atle vB
authors.initials: Av
authors.lastname: Granlund
authors.forename: Bjørn I
authors.initials: BI
authors.lastname: Gustafsson
authors.forename: Sverre H
authors.initials: SH
authors.lastname: Torp
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.forename: Tom E
authors.initials: TE
authors.lastname: Mollnes
authors.forename: Jan K
authors.initials: JK
authors.lastname: Damås
authors.forename: Arne K
authors.initials: AK
authors.lastname: Sandvik
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D002986:Clinical Trials as Topic; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology*; D011415:Complement Factor B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011070:Poly I-C / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome; D055815:Young Adult
chemical_list: D007369:Interferon Inducers; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D011415:Complement Factor B; D011070:Poly I-C