Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin

Endocrinology. 2007 Nov;148(11):5478-86. doi: 10.1210/en.2007-0370. Epub 2007 Aug 16.

Abstract

Adipose tissue secretes a wide range of hormones named adipokines, and these may play a role in obesity-related inflammation. Adiponectin is an exceptional adipokine because low plasma concentrations are associated with obesity, type 2 diabetes, and cardiovascular diseases. It has been observed that plasma adiponectin concentrations are elevated during inflammatory conditions like preeclampsia and arthritis. Nuclear factor-kappaB (NF-kappaB) is an essential transcription factor for expression of inflammation-related proteins. We have used U937 cells stably transfected to express luciferase under the control of NF-kappaB to examine if adiponectin may modulate NF-kappaB activity. Physiological concentrations of native adiponectin induced NF-kappaB activity. This effect was relatively strong compared with proinflammatory adipokines like leptin, resistin, and IL-6. The enhanced NF-kappaB activity was attributed to the high molecular weight adiponectin isoforms. NF-kappaB was not activated by mutated adiponectin that is unable to form high molecular weight complexes. Furthermore, the C-terminal fragment, globular adiponectin, markedly increased NF-kappaB reporter activity, cytokine release, and mRNA expression of inflammation marker genes, at higher levels than stimulation with TNF-alpha and lipopolysaccharide. NF-kappaB activation by globular adiponectin was not affected by antibody inhibition of toll-like receptor 4 or TNF receptors 1 and 2 but was attenuated by inhibitors of p38 MAPK, phosphatidylinositol 3-kinase, and protein kinase C. Analyses of the p65 subunit of NF-kappaB in different leukocyte cell lines showed activation of two monocytic cell lines (U937 and THP-1) by native and globular adiponectin. Our results indicate that adiponectin has proinflammatory properties in monocytic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / chemistry
  • Adiponectin / pharmacology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Humans
  • Inflammation Mediators / metabolism
  • Jurkat Cells
  • Lipopolysaccharides / pharmacology
  • Molecular Weight
  • Monocytes / drug effects
  • Monocytes / metabolism
  • NF-kappa B / metabolism*
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein Folding*
  • Protein Isoforms / pharmacology
  • Protein Kinase C / physiology
  • Protein Transport / drug effects
  • RNA, Messenger / metabolism
  • U937 Cells
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • ADIPOQ protein, human
  • Adiponectin
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • Protein Isoforms
  • RNA, Messenger
  • Phosphatidylinositol 3-Kinases
  • Protein Kinase C
  • p38 Mitogen-Activated Protein Kinases