Cyclosporine, FK506, mycophenolate mofetil, and prednisolone differentially modulate cytokine gene expression in human airway-derived epithelial cells.
BACKGROUND
The immunosuppressive effects of cyclosporine (CsA), tacrolimus (FK506), mycophenolate mofetil (MMF), and prednisolone in cells from the immunological compartment are well documented. In contrast, limited information is available with respect to the effects of these immunosuppressive drugs on airway-epithelial cells, although these cells may contribute to the development of obliterative bronchiolitis (OB) through the production of interleukin (IL)-6 and IL-8.


METHODS
We studied the production of IL-6 and IL-8 proteins by airway-derived epithelial cell lines and primary epithelial cell cultures obtained from lung brushings. Transcriptional mechanisms were detected by transient transfections.


RESULTS
We demonstrate that CsA dose dependently induces the production of the proinflammatory cytokines IL-6 and IL-8 in both cell lines and primary epithelial cells. FK506 and MMF were also able to upregulate IL-8, although the effect was less dramatic than observed for CsA. Low concentrations of prednisolone (0.01 and 0.001 microg/ml) enhanced IL-6 and IL-8 secretion, whereas concentrations > or =0.01 microg/ml significantly diminished IL-6 secretion. Furthermore, we showed that CsA and prednisolone mediate their effects at the transcriptional level.


CONCLUSIONS
The data provide evidence that relevant concentrations of CsA and MMF in vivo may enhance the inflammatory processes in the lower airways of patients after lung transplantation.
Borger
P
P
Department of Pathology and Clinical Medicine, University Hospital Groningen, The Netherlands. P.Borger@path.azg.nl
Kauffman
H F
HF
Timmerman
J A
JA
Scholma
J
J
van den Berg
J W
JW
Koëter
G H
GH
D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008168:Lung / Q000166:cytology / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology; D012143:Respiratory Physiological Phenomena; D012137:Respiratory System / Q000166:cytology; D016559:Tacrolimus / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D016207:Cytokines; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D016209:Interleukin-8; D016572:Cyclosporine; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus