Vasoactive Intestinal Peptide

Vasoactive intestinal peptide is a 28-amino-acid neuropeptide, isolated in 1970 from pig intestine and named for what it was first observed to do: widen blood vessels. That name has aged badly, because the vasodilation is among the least interesting things about it.

It is produced by neurons throughout the body — in the gut wall, the lungs, blood vessels and the brain — and released from nerve endings as a transmitter. It acts on two receptors, VPAC1 and VPAC2, which belong to the same structural family as the receptors for GLP-1 and other metabolic hormones, and it causes smooth muscle to relax wherever it acts.

What made it a subject of immunology is that immune cells carry those receptors too. VIP is among the most potent anti-inflammatory signals identified, capable of shifting a response away from aggressive inflammation and toward tolerance. A molecule arriving from nerves and instructing immune cells is a concrete demonstration that the nervous and immune systems are one communicating network rather than two adjacent ones.

• Nerves instructing immune cells: Immune cells carrying receptors for a neurotransmitter is direct evidence of neuroimmune communication, which is one of the more significant shifts in how both systems are understood.

• Shifting the type of response: It is reported to move immune activity away from inflammation and toward regulation. Changing the character of a response is different from suppressing it, and it is what makes this peptide distinctive.

• Airway and vascular smooth muscle: It relaxes smooth muscle in airways and blood vessels, which is why it has been examined in pulmonary research quite separately from its immune role.

• Two receptors, different distributions: VPAC1 and VPAC2 are found in different tissues and on different immune cell types, so where the peptide arrives determines which of its several effects predominates.

The nervous system was long treated as separate from the immune system — one handling signals and sensation, the other handling defence. That separation turned out to be wrong. Nerves reach into lymph nodes, the gut wall and the lungs, and immune cells carry receptors for the transmitters those nerves release. VIP is one of the clearest examples of the crossover.

Its receptors are seven-pass membrane proteins that raise cyclic AMP inside the cell when engaged. In a smooth muscle cell, raised cyclic AMP causes relaxation — which is the vasodilation the peptide was named for, and the airway effect studied in respiratory research. In an immune cell the same internal messenger has a quite different consequence.

There, raising cyclic AMP suppresses the production of inflammatory signalling molecules and encourages the development of regulatory cells — the ones whose job is restraining a response rather than mounting one. The result is a shift in the type of immune reaction rather than a simple reduction in it, which is why VIP is described as promoting tolerance. One signal, one internal messenger, opposite-seeming outcomes decided entirely by which cell receives it.

The fundamental biology is well established and mainstream: its sequence, its receptors, its distribution in nerves, its effect on smooth muscle and its anti-inflammatory action on immune cells are all supported by extensive independent work spanning fifty years.

A synthetic version has been evaluated in respiratory conditions without leading to approval in the UK or EU, and clearance within minutes makes sustained delivery difficult. It is supplied for laboratory research only. The biology is not in doubt: its receptors, distribution and anti-inflammatory action on immune cells rest on fifty years of independent work, which makes it the reference compound for neuroimmune signalling.

KPV and LL-37 act on inflammation from within the immune system itself — one on the transcriptional switch inside a cell, the other on bacterial membranes outside. This peptide arrives from the nervous system entirely, which is the distinction worth holding.

Thymosin Alpha-1 also shapes the character of an immune response rather than its magnitude, and reading the two together shows two quite different routes to the same kind of influence.