Sulfasalazine and BAY 11-7082 interfere with the nuclear factor-kappa B and I kappa B kinase pathway to regulate the release of proinflammatory cytokines from human adipose tissue and skeletal muscle in vitro.
There is much evidence to indicate a role for adipocytokines in insulin resistance and/or type 2 diabetes mellitus. In experimental models, oral salicylates, through their ability to interfere with the nuclear factor-kappa B (NF-kappa B) transcription pathway, have been demonstrated to reverse insulin resistance. The aim of this study was to investigate whether NF-kappa B regulates the release of adipocytokines in human adipose tissue and skeletal muscle. Human sc adipose tissue and skeletal muscle (obtained from normal pregnant women) were incubated in the absence (control) or presence of two NF-kappa B inhibitors sulfasalazine (1.25, 2.5, and 5 mm) and BAY 11-7082 (25, 50, and 100 microm). After an 18-h incubation, the tissues were collected, and NF-kappa B p65 DNA-binding activity and I kappa B kinase (IKK-beta) and insulin receptor-beta protein expression were assessed by ELISA and Western blotting, respectively. The incubation medium was collected, and the release of TNF-alpha, IL-6, IL-8, resistin, adiponectin, and leptin was quantified by ELISA. Treatment of adipose tissue and skeletal muscle with sulfasalazine and BAY 11-7082 significantly inhibited the release of IL-6, IL-8, and TNF-alpha; NF-kappa B p65 DNA-binding activity; and IKK-beta protein expression (P < 0.05, by Newman-Keuls test). There was no effect of sulfasalazine and BAY 11-7082 on resistin, adiponectin, or leptin release. Both sulfasalazine and BAY 11-7082 increased the adipose tissue and skeletal muscle expression of insulin receptor-beta. The data presented in this study demonstrate that the IKK-beta/NF-kappa B transcription pathway is a key regulator of IL-6, IL-8, and TNF-alpha release from adipose tissue and skeletal muscle. Control of the IKK-beta/NF-kappa B pathway may therefore provide an alternative therapeutic strategy for regulating aberrant cytokine release and thereby alleviating insulin resistance in type 2 diabetes mellitus.
Lappas
Martha
M
Department of Obstetrics and Gynecology, University of Melbourne and Mercy Perinatal Research Center, Mercy Hospital for Women, 126 Clarendon Street, East Melbourne, 3002 Victoria, Australia. mlappas@unimelb.edu.au
Yee
Kirin
K
Permezel
Michael
M
Rice
Gregory E
GE
D052242:Adiponectin; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism*; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D006729:Hormones, Ectopic / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D011247:Pregnancy; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D052243:Resistin; D012460:Sulfasalazine / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D052242:Adiponectin; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D020738:Leptin; D016328:NF-kappa B; D009570:Nitriles; C499624:RETN protein, human; D052243:Resistin; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D012460:Sulfasalazine; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human