Sesquiterpene lactones inhibit Yersinia invasin protein-induced IL-8 and MCP-1 production in epithelial cells.
Enteric Yersinia bacteria trigger transcription and secretion of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in epithelial cells. Both chemokines are controlled by NF-kappaB. The NF-kappaB-binding site in the IL-8 promoter preferentially binds Rel p65/p65 homodimers and p50/p65 heterodimers while the NF-kappaB-binding motifs of the MCP-1 promoter preferably bind p50/p65 heterodimers and p50/p50 homodimers. Sesquiterpene lactones inhibit the transcription factor NF-kappaB by alkylating the p65 subunit. In this study we investigated the inhibitory effects of sesquiterpene lactones and the NF-kappaB inhibitor SN50 on NF-kappaB p50 and p65 subunits in Yersinia-triggered IL-8 and MCP-1 production. The sesquiterpene lactones blocked Yersinia-triggered IL-8 and MCP-1 production in a dose-dependent manner. In contrast, SN50 inhibited IL-8 production at high concentrations whereas it diminished the amount of secreted MCP-1 significantly already at low concentrations. By means of electrophoretic mobility shift assays we demonstrate that sesquiterpene lactones inhibit Yersinia-triggered activation of NF-kappaB by inhibiting Rel p65, but not Rel p50. Our results also demonstrate that SN50 is useful for inhibition of nuclear translocation of the NF-kappaB p50 subunit but cannot be considered a general NF-kappaB inhibitor.
Grassl
Guntram A
GA
Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Universitätsklinikum Tübingen, Elfriede-Aulhorn-Str. 6, D-72060 Tübingen, Germany.
Fessele
Sabine
S
Merfort
Irmgard
I
Lindenmeyer
Maja T
MT
Castro
Victor
V
Murillo
Renato
R
Nelson
Peter J
PJ
Autenrieth
Ingo B
IB
D018829:Adhesins, Bacterial / Q000276:immunology*; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D012717:Sesquiterpenes / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D015008:Yersinia enterocolitica / Q000276:immunology*
D018829:Adhesins, Bacterial; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016209:Interleukin-8; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D010455:Peptides; D012333:RNA, Messenger; C118258:SN50 peptide; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; C053476:invasin, Yersinia; D004247:DNA