Anti-inflammatory effects of thiazolidinediones in human airway smooth muscle cells.
Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dose-dependently reduced the IL-1β-induced release of IL-6 and vascular endothelial growth factor, the TNF-α-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-α-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-γ (PPARγ), these anti-inflammatory effects were not affected by a specific PPARγ inhibitor (GW 9662) or by the knockdown of PPARγ using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the anti-inflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARγ or AMPK.
Zhu
Ming
M
Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115-6021, USA.
Flynt
Lesley
L
Ghosh
Sanjukta
S
Mellema
Matt
M
Banerjee
Audreesh
A
Williams
Erin
E
Panettieri
Reynold A
RA
Shore
Stephanie A
SA
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012137:Respiratory System / Q000378:metabolism* / Q000473:pathology; D012265:Ribonucleotides / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014740:Vidarabine / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000893:Anti-Inflammatory Agents; D000963:Antimetabolites; D002839:Chromans; D016207:Cytokines; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D047495:PPAR gamma; D011720:Pyrazoles; D011743:Pyrimidines; D012265:Ribonucleotides; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D014740:Vidarabine; D000077288:Troglitazone