Transcriptional down-regulation of tumor necrosis factor-alpha gene expression by a synthetic peptide homologous to retroviral envelope protein.
We have previously shown that a synthetic peptide (CKS-17) homologous to retroviral envelope protein suppresses the accumulation of superantigen staphylococcal enterotoxin-induced TNF-alpha mRNA in human PBMC and in highly purified human monocytes. The present study was designed to examine the underlying mechanism(s) by which CKS-17 down-regulates the TNF-alpha mRNA expression using a human acute monocytic leukemia cell line THP-1 stimulated with the superantigen staphylococcal enterotoxin E. A cyclooxygenase inhibitor indomethacin does not reverse the inhibition of TNF-alpha mRNA expression by CKS-17, suggesting that prostaglandins are not responsible for the suppressive action of CKS-17. The inhibitory effect of CKS-17 is, however, significantly blocked by a protein synthesis inhibitor cycloheximide, indicating that CKS-17 requires de novo protein synthesis to induce the suppressive activity. The mRNA stability assays using actinomycin D show that CKS-17 does not decrease the TNF-alpha mRNA stability. Nuclear run-on transcription assays further reveal that CKS-17 suppresses the TNF-alpha mRNA transcription rate. Taken together, these results suggest that the synthetic retroviral peptide CKS-17 down-regulates TNF-alpha mRNA expression through inhibition of transcriptional activation of the TNF-alpha gene, which requires de novo synthesis of a transcriptional repressor protein(s).
Haraguchi
S
S
Department of Pediatrics, All Children's Hospital, University of South Florida, St. Petersburg 33701.
Good
R A
RA
Cianciolo
G J
GJ
James-Yarish
M
M
Day
N K
NK
D000595:Amino Acid Sequence; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation; D004768:Enterotoxins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000235:genetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D015682:Retroviridae Proteins, Oncogenic / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014759:Viral Envelope Proteins / Q000494:pharmacology*
D004768:Enterotoxins; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D010455:Peptides; D015682:Retroviridae Proteins, Oncogenic; D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins; C049463:enterotoxin E, Staphylococcal; D003513:Cycloheximide; C053692:CKS 17; D007213:Indomethacin