Down-regulation by troglitazone of hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression in a murine model of non-insulin-dependent diabetes.
Troglitazone, a novel thiazolidinedione drug used to treat non-insulin-dependent diabetes mellitus, is a selective ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). Recent results indicate that PPARgamma activation by thiazolidinediones regulates adipose tissue- and monocyte/peritoneal macrophage-derived cytokine expression in vitro. We evaluated whether troglitazone may also negatively regulate cytokine expression in the liver, which harbors the majority of the body's resident macrophages but which only weakly expresses PPARgamma. Lean C57BL6 mice and genetically obese KKA(y) mice were chronically treated with troglitazone (100 mg/kg/day for 2 weeks). At the end of treatment, hepatic expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 mRNA was quantitatively determined by kinetic polymerase chain reaction both under basal conditions and after stimulation with lipopolysaccharide (LPS). Both untreated lean and obese mice exhibited low levels of baseline TNF-alpha and IL-6 mRNA expression and responded with a dramatic increase in hepatic cytokine transcripts and TNF-alpha protein expression following a challenge with LPS. Similar to the effects on white adipose tissue, troglitazone not only down-regulated the baseline levels of hepatic TNF-alpha and IL-6, but also greatly attenuated the inducing effects of LPS. The extent of this inhibitory effect of troglitazone was higher in obese KKA(y) mice than in lean mice and was also reflected by markedly down-regulated hepatic TNF-alpha protein expression. These data demonstrate that chronic administration of troglitazone is associated with a greatly attenuated responsiveness towards inducers of hepatic TNF-alpha and IL-6 production. The possible biological consequences of these effects, however, have not yet been assessed.
Sigrist
S
S
Department of Non-Clinical Drug Safety, F. Hoffmann-La Roche AG, CH-4070, Basel, Switzerland.
Bedoucha
M
M
Boelsterli
U A
UA
D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D002839:Chromans; D007004:Hypoglycemic Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077288:Troglitazone