Peptide-mediated disruption of NFkappaB/NRF interaction inhibits IL-8 gene activation by IL-1 or Helicobacter pylori.
Selective inhibition of proinflammatory chemokines such as IL-8 is an important approach to combat inflammatory and infection diseases. Previous studies suggested that interaction of transcription factors NFkappaB repressing factor (NRF) and NFkappaB play a crucial role in activation of IL-8 gene expression. In a search for a specific inhibitor of IL-8 expression, we applied tandem affinity purification to investigate interaction of NRF and NFkappaB p65 in cells. We identified a synthetic peptide corresponding to aa 223-238 of NRF interfering with binding of endogenous p65 to NRF. Furthermore, nucleofection experiments were established to introduce this inhibitory peptide into the nucleus of IL-1 stimulated human cervical and Helicobacter pylori infected gastric epithelial cells. Our data clearly show that the specific peptide disturbing NRF/NFkappaB interaction is able to significantly decrease endogenous IL-8 gene transcription in response to IL-1 or Helicobacter pylori infection. Thus, our study provides novel insights into NRF and NFkappaB interaction in vivo and may facilitate the design of new anti-IL-8 drugs based on novel strategies.
Bartels
Myriam
M
Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
Schweda
Aike Torben
AT
Dreikhausen
Ursula
U
Frank
Ronald
R
Resch
Klaus
K
Beil
Winfried
W
Nourbakhsh
Mahtab
M
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D020869:Gene Expression Profiling; D006367:HeLa Cells; D016481:Helicobacter Infections / Q000276:immunology / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D011485:Protein Binding; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; C111027:NKRF protein, human; D010455:Peptides; D012097:Repressor Proteins