title: The inflammasome and caspase-1 activation: a new mechanism underlying increased inflammatory activity in human visceral adipose tissue.
abstract: The immune competent abdominal adipose tissue, either stored viscerally [visceral adipose tissue (VAT)] or sc [sc adipose tissue (SAT)], has been identified as a source of IL-1β and IL-18. To become active, the proforms of these cytokines require processing by caspase-1, which itself is mediated by the inflammasome. In this descriptive study, we investigate the expression of inflammasome components and caspase-1 in human fat and determine whether caspase-1 activity contributes to the enhanced inflammatory status of VAT. Paired SAT and VAT biopsies from 10 overweight subjects (body mass index, 25-28 kg/m(2)) were used to study the cellular composition and the intrinsic inflammatory capacity of both adipose tissue depots. The percentage of CD8(+) T cells within the lymphocyte fraction was significantly higher in VAT compared with SAT (41.6 vs. 30.4%; P < 0.05). Adipose tissue cultures showed a higher release of IL-1β (10-fold; P < 0.05), IL-18 (3-fold; P < 0.05), and IL-6 and IL-8 (3-fold, P < 0.05; and 4-fold, P < 0.05, respectively) from VAT compared with SAT that was significantly reduced by inhibiting caspase-1 activity. In addition, caspase-1 activity was 3-fold (P < 0.05) higher in VAT compared with SAT, together with an increase in the protein levels of the inflammasome members apoptosis-associated speck-like protein containing a C-terminal caspase-recruitment domain (2-fold; P < 0.05) and nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (2-fold; nonsignificant). Finally, caspase-1 activity levels were positively correlated with the percentage of CD8(+) T cells present in adipose tissue. Our results show that caspase-1 and nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 inflammasome members are abundantly present in human VAT. The increased intrinsic caspase-1 activity in VAT represents a novel and specific inflammatory pathway that may determine the proinflammatory character of this specific depot.
authors.affiliation: Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Internal Postal Code 463, Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands. t.koenen@aig.umcn.nl
authors.forename: Tim B
authors.initials: TB
authors.lastname: Koenen
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.forename: Lambertus J
authors.initials: LJ
authors.lastname: van Tits
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Jeroen F
authors.initials: JF
authors.lastname: van Velzen
authors.forename: Anneke
authors.initials: A
authors.lastname: Hijmans
authors.forename: Jillis A
authors.initials: JA
authors.lastname: Pol
authors.forename: J A
authors.initials: JA
authors.lastname: van der Vliet
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.forename: Anton F H
authors.initials: AF
authors.lastname: Stalenhoef
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Graaf
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D020170:Caspase 1 / Q000502:physiology*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D007249:Inflammation / Q000209:etiology*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000201:enzymology / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D050151:Subcutaneous Fat / Q000276:immunology
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D020170:Caspase 1