FTY720 suppresses interleukin-1beta-induced secretory phospholipase A2 expression in renal mesangial cells by a transcriptional mechanism.
OBJECTIVE
FTY720 is a potent immunomodulatory prodrug that is converted to its active phosphorylated form by a sphingosine kinase. Here we have studied whether FTY720 mimicked the action of sphingosine-1-phosphate (S1P) and exerted an anti-inflammatory potential in renal mesangial cells.


METHODS
Prostaglandin E(2) (PGE(2)) was quantified by an enzyme-linked immunosorbent-assay. Secretory phospholipase A(2) (sPLA(2)) protein was detected by Western blot analyses. mRNA expression was determined by Northern blot analysis and sPLA(2)-promoter activity was measured by a luciferase-reporter-gene assay.


RESULTS
Stimulation of cells for 24 h with interleukin-1beta (IL-1beta) is known to trigger increased PGE(2) formation which coincides with an induction of the mRNA for group-IIA-sPLA(2) and protein expression. FTY720 dose-dependently suppressed IL-1beta-induced IIA-sPLA(2) protein secretion and activity in the supernatant. This effect is due to a suppression of cytokine-induced sPLA(2) mRNA expression which results from a reduced promoter activity. As a consequence of suppressed sPLA(2) activity, PGE(2) formation is also reduced by FTY720. Mechanistically, the FTY720-suppressed sPLA(2) expression results from an activation of the TGFbeta/Smad signalling cascade since inhibition of the TGFbeta receptor type I by a specific kinase inhibitor reverses the FTY720-mediated decrease of sPLA(2) protein expression and sPLA(2) promoter activity.


CONCLUSIONS
In summary, our data show that FTY720 was able to mimic the anti-inflammatory activity of TGFbeta and blocked cytokine-triggered sPLA(2) expression and subsequent PGE(2) formation. Thus, FTY720 may exert additional in vivo effects besides the well reported immunomodulation and its anti-inflammatory potential should be considered.
Xin
C
C
Institute of Pharmacology, University of Bern, Bern, Switzerland.
Ren
S
S
Eberhardt
W
W
Pfeilschifter
J
J
Huwiler
A
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D000068876:Fingolimod Hydrochloride; D054501:Group II Phospholipases A2; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054467:Phospholipases A2; D011409:Propylene Glycols / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D011409:Propylene Glycols; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016718:Arachidonic Acid; C012589:trichostatin A; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine