Resistin, an adipokine with potent proinflammatory properties.
The adipokine resistin is suggested to be an important link between obesity and insulin resistance. In the present study, we assessed the impact of resistin as inflammatogenic cytokine in the setting of arthritis. In vitro experiments on human PBMC were performed to assess cytokine response and transcription pathways of resistin-induced inflammation. Proinflammatory properties of resistin were evaluated in animal model by intra-articular injection of resistin followed by histological evaluation of the joint. Levels of resistin were assessed by ELISA in 74 paired blood and synovial fluid samples of patients with rheumatoid arthritis. Results were compared with the control group comprised blood samples from 34 healthy individuals and 21 synovial fluids from patients with noninflammatory joint diseases. We now show that resistin displays potent proinflammatory properties by 1) strongly up-regulating IL-6 and TNF-alpha, 2) responding to TNF-alpha challenge, 3) enhancing its own activity by a positive feedback, and finally 4) inducing arthritis when injected into healthy mouse joints. Proinflammatory properties of resistin were abrogated by NF-kappaB inhibitor indicating the importance of NF-kappaB signaling pathway for resistin-induced inflammation. Resistin is also shown to specifically accumulate in the inflamed joints of patients with rheumatoid arthritis and its levels correlate with other markers of inflammation. Our results indicate that resistin is a new and important member of the cytokine family with potent regulatory functions. Importantly, the identified properties of resistin make it a novel and interesting therapeutic target in chronic inflammatory diseases such as rheumatoid arthritis.
Bokarewa
Maria
M
Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy at Göteborg University, Sweden. maria.bokarewa@rheuma.gu.se
Nagaev
Ivan
I
Dahlberg
Leif
L
Smith
Ulf
U
Tarkowski
Andrej
A
D017667:Adipocytes / Q000276:immunology* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D006729:Hormones, Ectopic / Q000008:administration & dosage / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000502:physiology*; D007270:Injections, Intra-Articular; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D052243:Resistin; D015398:Signal Transduction / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D006729:Hormones, Ectopic; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; C499624:RETN protein, human; D011994:Recombinant Proteins; D052243:Resistin; C499623:Retn protein, mouse; D014409:Tumor Necrosis Factor-alpha