Two Peptides — Hemokinin-1 and Substance P — Drive Inflammatory Signaling in Human Colon Tissue

What the researchers found

When human colonic mucosal tissue was exposed to hemokinin-1 (HK-1) at 0.1 μM for 4 hours, it significantly increased both gene expression and release of multiple inflammatory mediators: MCP-1, MIP-1α, MIP-1β, RANTES, TNF-α, IL-1β, and IL-6.

Substance P (SP) at the same concentration produced comparable effects on most mediators but notably did not affect MCP-1 or RANTES — indicating HK-1 has a broader pro-inflammatory profile than SP in the human colon.

Both NK1 receptor antagonist SR140333 and NK2 receptor antagonist SR48968 (each at 0.1 μM) separately inhibited these inflammatory responses, demonstrating that both receptor types mediate the effects. This dual-receptor involvement was a novel finding and suggests HK-1 may also signal through additional tachykinin-preferring receptors.

Why it matters

Inflammatory bowel disease (IBD) affects millions of people, and understanding what drives gut inflammation is essential for developing better treatments. This study reveals that HK-1, a peptide primarily from immune cells, may be an important inflammatory driver in the colon — potentially even more so than the better-known substance P. Since both peptides work through identifiable receptors, this opens the door to developing receptor-blocking drugs that could calm gut inflammation.

How the study worked

The researchers used human colonic mucosal explants — tissue samples taken from human colons — and incubated them with HK-1 or substance P at 0.1 μM for 4 hours. They measured inflammatory cytokine and chemokine production at both the gene expression level (using QuantiGene assay) and the protein release level (using Procarta multiplex assay). To determine which receptors were involved, they pre-treated tissue with selective NK1 (SR140333) or NK2 (SR48968) receptor antagonists before peptide exposure.

What this study cannot tell us

This is an ex vivo study using isolated tissue explants, which may not fully represent the complex in vivo environment of the gut. The tissue was exposed to peptides for only 4 hours, so longer-term effects are unknown. The sample size and donor demographics are not fully detailed in the abstract. The study does not include tissue from IBD patients, so the relevance to active disease is inferred rather than directly demonstrated. Concentration tested (0.1 μM) may not reflect physiological levels.

How to read the evidence

This is an ex vivo mechanistic study using human tissue, which provides more relevant data than cell lines or animal tissue but cannot establish clinical causation. The use of receptor antagonists strengthens the mechanistic conclusions, but the findings need validation in vivo and in disease-state tissue.

When this study was published

Published in 2020, this study is relatively recent. Research on HK-1's role in human gut inflammation is still an emerging area, and these findings may have informed subsequent work on tachykinin receptor targeting in IBD.

The bigger picture

The tachykinin peptide family has long been studied in pain and neurogenic inflammation, but its role in gut immune responses is gaining attention. This study positions HK-1 — which comes from immune cells rather than neurons — as a potentially important player in colonic inflammation alongside the neuronal peptide substance P. Understanding both immune-derived and nerve-derived inflammatory peptides could lead to more comprehensive anti-inflammatory strategies for IBD that target multiple pathways simultaneously.

Questions still open

• Are HK-1 levels elevated in colon tissue from patients with active inflammatory bowel disease compared to healthy controls?
• Would dual NK1/NK2 receptor antagonists be more effective than single-receptor blockers for treating colonic inflammation?
• Does HK-1 play different inflammatory roles in other parts of the gastrointestinal tract beyond the colon?

Common questions

Read the original research

Hemokinin-1 and substance P stimulate production of inflammatory cytokines and chemokines in human colonic mucosa via both NK1 and NK2 tachykinin receptors.

Neuropeptides, 82, 102061

Citation

Dai, Liying; Perera, D Shevy; Burcher, Elizabeth; Liu, Lu. (2020). Hemokinin-1 and substance P stimulate production of inflammatory cytokines and chemokines in human colonic mucosa via both NK1 and NK2 tachykinin receptors.. Neuropeptides, 82, 102061. https://doi.org/10.1016/j.npep.2020.102061