Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway.
Resistin, a recently discovered 92 amino acid protein involved in the development of insulin resistance, has been associated with obesity and type 2 diabetes. The elevated serum resistin in human diabetes is often associated with a pro-inflammatory milieu. However, the role of resistin in the development of inflammation is not well understood. Addition of recombinant human resistin protein (hResistin) to macrophages (both murine and human) resulted in enhanced secretion of pro-inflammatory cytokines, TNF-alpha and IL-12, similar to that obtained using 5 microg/ml lipopolysaccharide. Both oligomeric and dimeric forms of hResistin were able to activate these cytokines suggesting that the inflammatory action of resistin is independent of its conformation. Heat denatured hResistin abrogated cytokine induction while treatment of recombinant resistin with polymyxin B agarose beads had no effect thereby ruling out the role of endotoxin in the recombinant hResistin mediated cytokine induction. The pro-inflammatory nature of hResistin was further evident from the ability of this protein to induce the nuclear translocation of NF-kappaB transcription factor as seen from electrophoretic mobility shift assays. Induction of TNF-alpha in U937 cells by hResistin was markedly reduced in the presence of either dominant negative IkappaBalpha plasmid or PDTC, a pharmacological inhibitor of NF-kappaB. A protein involved in conferring insulin resistance is also a pro-inflammatory molecule that has important implications.
Silswal
Nirupama
N
Molecular Biology Unit, National Institute of Nutrition (ICMR), Hyderabad 500007, India.
Singh
Anil K
AK
Aruna
Battu
B
Mukhopadhyay
Sangita
S
Ghosh
Sudip
S
Ehtesham
Nasreen Z
NZ
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D006729:Hormones, Ectopic / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D052243:Resistin; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D020298:U937 Cells
D016207:Cytokines; D006729:Hormones, Ectopic; D016328:NF-kappa B; C499624:RETN protein, human; D011994:Recombinant Proteins; D052243:Resistin; C499623:Retn protein, mouse; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12