Substance P induces TNF-α and IL-6 production through NFκB 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 (NFkappaB). The tumour necrosis factor-alpha (TNF-alpha) and IL-6 production was completely inhibited by using (E)-4-hydroxynonenal (HNE) as an inhibitor of IkappaB-alpha and -beta phosphorylation. Further, TNF-alpha and IL-6 expression was significantly inhibited by the oligonucleotides (ODNs) containing the NFkappaB element (NFkappaB decoy ODNs) but not by the scrambled control ODNs. These findings indicate that the NFkappaB pathway is involved in the transcriptional regulation of the TNF-a and IL-6 overexpression in primary SP-stimulated mast cells. (C) 2003 Elsevier B.V All rights reserved.