Upstream eventSP (Substance P) release, Local increase of SP
Non-neuronal production of TNF, Epithelial irritation
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Local substance P released from nociceptive neurons stimulates non-neuronal cells, thought to be mostly myeloid immune cells such as macrophages and mast cells, to secrete TNF. This is thought to underpin neurogenic inflammation observed following strong stimulation by irritant chemicals.
Evidence Supporting this KER
Substance P acts through neurokinin 1 receptors (NK-1R) on target cells. It has been shown that NK-1R may activate NF-kB, which is well-known to signal TNF production.
It has been shown in a number of in vitro and ex vivo models that substance P can cause myeloid cells to produce TNF and substance P levels have been frequently correlated in tissue in vivo (Luber-Narod et al, 1994, Nair and Schwartz, 1995, Bardelli et al, 2005, Sipos et al, 2008).
Uncertainties and Inconsistencies
There are reports of production of substance P by non-neuronal cells. Although it can be maintained that neurons are the principal source of substance P, it cannot be ruled out that other cell types may produce substance P in response to irritant chemicals.
Quantitative Understanding of the Linkage
TNF release induced by substance P can be demonstrated as dose-responsive. As with most immune-related pathways, the sensitivity of TNF production following cellular exposure to a specific stimulus may be modulated by other cell signaling pathways.