API

Relationship: 1279

Title

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SP (Substance P) release, Local increase of SP leads to Non-neuronal production of TNF, Epithelial irritation

Upstream event

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SP (Substance P) release, Local increase of SP

Downstream event

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Non-neuronal production of TNF, Epithelial irritation

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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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

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Biological Plausibility

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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.

Empirical Evidence

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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

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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

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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.

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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