Peptide inhibition of a cytokine response

Excerpt

Activation of genes encoding tumour necrosis factor (TNF)-a, interferon (IFN)-? or interleukin (IL)-1 in response to pro-inflammatory agonists involves the nuclear translocation of SRTFs such as nuclear factor kappa B (NF?B) or nuclear factor of activated T cells (NFAT), and their subsequent interaction with the promoter region of the specific gene. Disruption of the SRTF signalling pathway would suppress the expression of TNF-a and IFN-?, cytokines that are known to play a key role in the systemic inflammatory response syndrome induced by LPS. A linear peptide (SN50) containing a membrane translocation motif and a nuclear localisation sequence (NLS), derived from the p50-NF?B1 subunit of the transcription factor NF?B, was therefore designed and shown to inhibit the nuclear import of NF?B in human monocytic and murine endothelial cells stimulated with LPS or TNF-a. SN50 also inhibited the expression of downstream SRTF-regulated genes such as cycloxygenase and IL-2 in vitro and was shown to interact with a cytoplasmic NLS receptor comprised of the Rch 1/importin (karyopherin)-? heterodimer. To inhibit SRTF mediated inflammatory responses in vivo using a cyclic peptide. …