title: LPS-Stimulated Whole Blood Cytokine Production Is Not Related to Disease Behavior in Patients with Quiescent Crohn's Disease.
abstract: BACKGROUND
  Crohn's disease (CD) is a chronic inflammatory disease in which cytokines play a pivotal role in the induction and maintenance of inflammation. Innate cytokine production is genetically determined and varies largely between individuals; this might impact the severity of inflammation. We aimed to assess whether ex-vivo endotoxin-stimulated levels of cytokines could be associated with disease phenotype.
  
  
  METHODS
  Patients with quiescent CD (Harvey-Bradshaw Index ≤ 4 and negative inflammation markers) who were not using immunomodulating drugs or biologicals were eligible. Historical disease characteristics (localization, behavior, number of bowel resections, drug history, extra-intestinal symptoms) were extracted from medical records. We measured cytokine levels (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10) in supernatants of lipopolysaccharide (LPS) -stimulated whole blood cultures and correlated these with disease characteristics and age- and sex-matched healthy controls. In addition, we analyzed whether single nucleotide polymorphisms (SNPs) in the promoter region of the TNF-α gene were related to TNF-α levels.
  
  
  RESULTS
  We included 75 patients with CD and 24 healthy controls. Six patients were excluded because of increased inflammation markers resulting in a total of 69 patients. The mean age (SD) of patients with CD was 51.2 (12.3) years with a mean (SD) disease duration of 24.1 (11.5) years. Disease localization, peri-anal involvement and behavior were not related to LPS-stimulated TNF-α, IL-1β, IL-6 or IL-10 levels. In addition, combination of localization with behavior to differentiate mild from severe disease type showed no significant differences. TNF-α levels were higher in patients with CD (428 pg/ml IQR [267-468]) compared to healthy controls (459 pg/ml IQR [364-570], p=0.02). We found no associations between SNPs in the promoter region and TNF-α levels.
  
  
  CONCLUSIONS
  In this study, innate cytokine production of TNF-α, IL-1β, IL-6 and IL-10 was not related to historical disease characteristics or disease severity in patients with quiescent CD. These findings suggest that genetically determined levels of these cytokines obtained from LPS-stimulated whole blood cultures are not linked with disease behavior or severity.
authors.affiliation: Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Mark M T J
authors.initials: MM
authors.lastname: Broekman
authors.affiliation: Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Hennie M J
authors.initials: HM
authors.lastname: Roelofs
authors.affiliation: Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Hoentjen
authors.affiliation: Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Renske
authors.initials: R
authors.lastname: Wiegertjes
authors.affiliation: Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: Stoel
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Leo A
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: de Jong
authors.affiliation: Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Geert J A
authors.initials: GJ
authors.lastname: Wanten
mesh_terms: D016022:Case-Control Studies; D003424:Crohn Disease / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha