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Activation of Nuclear Factor-B by High Molecular Weight and Globular Adiponectin

Department of Nutrition, Institute of Basic Medical Sciences, Medical Faculty, University of Oslo, 0316 Oslo, Norway

Address all correspondence and requests for reprints to: Fred Haugen, Ph.D., Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046 Blindern, 0316 Oslo, Norway. E-mail: fred.haugen{at}medisin.uio.no.

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-B (NF-B) 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-B to examine if adiponectin may modulate NF-B activity. Physiological concentrations of native adiponectin induced NF-B activity. This effect was relatively strong compared with proinflammatory adipokines like leptin, resistin, and IL-6. The enhanced NF-B activity was attributed to the high molecular weight adiponectin isoforms. NF-B 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-B reporter activity, cytokine release, and mRNA expression of inflammation marker genes, at higher levels than stimulation with TNF- and lipopolysaccharide. NF-B 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-B 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.

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