Anti-inflammatory activity of 15-deoxy-delta12,14-PGJ2 and 2-cyclopenten-1-one: role of the heat shock response.
The transcription factor heat shock factor 1 (HSF1) plays a key role in the expression of several genes, such as heat shock protein (hsp) genes, which are cytoprotective against several pathological conditions, including inflammation. Cyclopentenone prostaglandins (cyPG) are able to activate HSF1 and induce the synthesis of the 70-kDa hsp (hsp70) in mammalian cells. These molecules are characterized by the presence of a reactive alpha,beta-unsatured carbonyl group in the cyclopentane ring (cyclopentenone) which is the key structure for triggering HSF1 activation. In the present study, we investigated, in carrageenin hind-paw edema, an acute model of inflammation, the effect of double-stranded oligodeoxynucleotides with consensus HSF1 sequence as transcription factor decoys to inhibit HSF1 binding to native DNA sites. We show that HSF1 activation and hsp72 expression occurs in inflamed tissue and that this effect is associated with the remission of the inflammatory reaction. Moreover, we studied the effect of prostaglandin 15-deoxy-delta12,14-prostaglandin (PG) J2, of its precursor, PGD2 and, for the first time in vivo, the effect of the cyclopentenone ring structure itself, 2-cyclopenten-1-one. Our results demonstrated that all agents used had anti-inflammatory properties and that this effect was associated with HSF1-induced hsp72 expression in vivo, suggesting that the use of cyclopentenone derivatives may represent a novel therapeutic approach to the treatment of inflammatory diseases.
Ianaro
Angela
A
Department of Experimental Pharmacology, University of Naples Federico II, Via D. Montesano 4, 80131, Naples, Italy. ianaro@unina.it
Ialenti
Armando
A
Maffia
Pasquale
P
Di Meglio
Paola
P
Di Rosa
Massimo
M
Santoro
M Gabriella
MG
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002351:Carrageenan; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D050884:HSP72 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D018869:Heat-Shock Response / Q000187:drug effects*; D008297:Male; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014157:Transcription Factors
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000893:Anti-Inflammatory Agents; D003517:Cyclopentanes; D004268:DNA-Binding Proteins; D050884:HSP72 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C000619709:Hsf1 protein, rat; D014157:Transcription Factors; D002351:Carrageenan; C013905:cyclopentenone; D015230:Prostaglandin D2