title: Inflammatory cytokines and hypoxia contribute to 18F-FDG uptake by cells involved in pannus formation in rheumatoid arthritis.
abstract: Assessment of the activity of rheumatoid arthritis (RA) is important for the prediction of future articular destruction. (18)F-FDG PET is known to represent the metabolic activity of inflammatory disease, which correlates with the pannus volume measured by MRI or ultrasonography. To evaluate the correlation between (18)F-FDG accumulation and RA pathology, we assessed (18)F-FDG accumulation in vivo using collagen-induced arthritis (CIA) animal models and (3)H-FDG uptake in vitro using various cells involved in arthritis.
  
  
  METHODS
  (18)F-FDG PET images of rats with CIA were acquired on days 10, 14, and 17 after arthritis induction. The specimens were subsequently subjected to macroautoradiography, and the (18)F-FDG accumulation was compared with the histologic findings. (3)H-FDG uptake in vitro in inflammatory cells (neutrophils, macrophages, T cells, and fibroblasts) was measured to evaluate the contributions of these cells to (18)F-FDG accumulation. In addition, the influence on (3)H-FDG uptake of inflammatory factors, such as cytokines (tumor necrosis factor alpha [TNFalpha], interleukin 1 [IL-1], and IL-6), and hypoxia was examined.
  
  
  RESULTS
  (18)F-FDG PET depicted swollen joints, and (18)F-FDG accumulation increased with the progression of arthritis. Histologically, a higher level of (18)F-FDG accumulation correlated with the pannus rather than the infiltration of inflammatory cells around the joints. In the in vitro (3)H-FDG uptake assay, fibroblasts showed the highest (3)H-FDG uptake, followed by neutrophils. Although only a small amount of (3)H-FDG was incorporated by resting macrophages, a dramatic increase in (3)H-FDG uptake in both fibroblasts and macrophages was observed when these cells were exposed to inflammatory cytokines, such as TNFalpha and IL-1, and hypoxia. Although neutrophils showed relatively high (3)H-FDG uptake without activation, no increase in (3)H-FDG uptake was observed in response to inflammatory cytokines. (3)H-FDG uptake by T cells was much lower than that by other cells. Thus, fibroblasts and activated macrophages contribute to a high level of (18)F-FDG accumulation in the pannus, and hypoxia as well as cytokine stimulation significantly increases (18)F-FDG uptake by these cells.
  
  
  CONCLUSIONS
  (18)F-FDG accumulation in RA reflects proliferating pannus and inflammatory activity enhanced by inflammatory cytokines and hypoxia. (18)F-FDG PET should be effective for quantifying the inflammatory activity of RA.
authors.affiliation: Research Center, Nihon Medi-physics Co., Ltd., Chiba, Japan.
authors.forename: Tamiko
authors.initials: T
authors.lastname: Matsui
authors.forename: Norihito
authors.initials: N
authors.lastname: Nakata
authors.forename: Shigenori
authors.initials: S
authors.lastname: Nagai
authors.forename: Akira
authors.initials: A
authors.lastname: Nakatani
authors.forename: Miwako
authors.initials: M
authors.lastname: Takahashi
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Momose
authors.forename: Kuni
authors.initials: K
authors.lastname: Ohtomo
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D016207:Cytokines; D019788:Fluorodeoxyglucose F18