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Pro-inflammatory properties for thiazolidinediones.
Christophe Desmet1, Barbara Warzée, Philippe Gosset
1Department of Physiology, Bât. B42, Molecular and Cellular Therapy Center, University of Liège, B-4000 Liège, Belgium.
Biochemical Pharmacology
|January 4, 2005
Summary
Thiazolidinediones (TZDs) used for diabetes may worsen inflammation. These drugs, like rosiglitazone and troglitazone, can increase inflammatory cytokine production in epithelial cells, contrary to previous assumptions.
Area of Science:
- Pharmacology
- Immunology
- Cell Biology
Background:
- Thiazolidinediones (TZDs) are established type II diabetes treatments, acting as peroxisome proliferator-activated receptor (PPAR)-gamma ligands.
- Emerging evidence suggested TZDs possess anti-inflammatory properties, potentially inhibiting pro-inflammatory cytokine expression and attenuating in vivo inflammatory responses.
Purpose of the Study:
- To investigate the effect of TZDs (rosiglitazone and troglitazone) on tumor necrosis factor (TNF)-alpha-induced inflammatory responses in epithelial cells.
- To determine if TZDs potentiate or inhibit inflammation mediated by TNF-alpha in epithelial cell models.
Main Methods:
- Exposure of various epithelial cell types to rosiglitazone (RSG) and troglitazone (TRO) in combination with TNF-alpha.
- Measurement of pro-inflammatory cytokine production (GM-CSF, IL-6, IL-8) and neutrophil pro-survival activity in cell supernatants.
- Analysis of cytokine expression at the transcriptional level and assessment of the role of PPARgamma, NF-kappaB, and MAPK pathways.
Main Results:
- Contrary to expectations, RSG and TRO did not inhibit TNF-alpha-induced inflammation; instead, they significantly potentiated the production of key pro-inflammatory cytokines.
- Co-treatment with TNF-alpha and TZDs resulted in enhanced neutrophil pro-survival activity in cell supernatants, indicating functional pro-inflammatory effects.
- TZDs were found to enhance cytokine expression transcriptionally, with these pro-inflammatory effects being independent of PPARgamma, NF-kappaB, or MAPK activation.
Conclusions:
- TZDs, specifically rosiglitazone and troglitazone, can potentiate the inflammatory response in epithelial cells, a previously unrecognized effect.
- This potentiation of inflammation occurs independently of the canonical PPARgamma pathway and other major inflammatory signaling cascades.
- The findings challenge the presumed anti-inflammatory role of TZDs and highlight a potential pro-inflammatory consequence in epithelial inflammatory settings.