Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells.

The neuropeptide Substance P (SP) is an important mediator of neuroimmunomodulatory activity. The aim of this study is to elucidate the mechanism used by SP to promote increased production of pro-inflammatory cytokines in fresh isolated rat peritoneal mast cells (rPMC). We have demonstrated that SP induces production of interleukin-6 (IL-6) in rPMC through the PI-3K, p42/44 and p38 MAP kinase pathways. SP-stimulated rPMC also exhibited an enhanced nuclear translocation of the nuclear factor kappa B (NF kappa B). The tumour necrosis factor-alpha (TNF-alpha) and IL-6 production was completely inhibited by using (E)-4-hydroxynonenal (HNE) as an inhibitor of I kappa B-alpha and -beta phosphorylation. Further, TNF-alpha and IL-6 expression was significantly inhibited by the oligonucleotides (ODNs) containing the NF kappa B element (NF kappa B decoy ODNs) but not by the scrambled control ODNs. These findings indicate that the NF kappa B pathway is involved in the transcriptional regulation of the TNF-alpha and IL-6 overexpression in primary SP-stimulated mast cells.