VIP vs LL-37
Vasoactive intestinal peptide is a 28-amino-acid neuropeptide signalling through the class B G protein-coupled receptors VPAC1 and VPAC2, with a clinical literature built around its synthetic form aviptadil in respiratory failure, sarcoidosis and erectile dysfunction. LL-37 is the sole human cathelicidin, a 37-residue amphipathic alpha-helical peptide released from the hCAP18 precursor, studied overwhelmingly as an antimicrobial and immunomodulatory effector. The pair is set side by side in protocol material about chronic inflammatory response syndromes, where both are described as immune peptides. Unusually for this category, one direct comparison exists: a 2011 bactericidal assay study tested vasoactive intestinal peptide and orexin B alone and in combination with LL-37 against four bacterial species at two salt concentrations. That single in vitro experiment is the whole of the head-to-head evidence, and the remaining publications engaging both are reviews that list them as ligands of the same mast-cell receptor or as members of the same peptide catalogue.
They have been compared directly.
Ohta and colleagues at the Forsyth Institute measured the bactericidal effects of orexin B and vasoactive intestinal peptide, alone and combined with cationic antimicrobial peptides including LL-37, against Escherichia coli, Pseudomonas aeruginosa, Streptococcus mutans and Staphylococcus aureus. Bactericidal activity of vasoactive intestinal peptide on its own was detected at low sodium chloride concentration but was attenuated at the physiological concentration of 150 mM. Adding LL-37 restored the attenuated activity, and the authors concluded that vasoactive intestinal peptide and orexin B appear to mediate bactericidal effects in concert with LL-37 in the physiological context of mucosal tissue. The result is additive and complementary rather than a ranking of one peptide against the other, and it was generated in bacterial killing assays rather than in cells, animals or people. A later review restated the same finding, noting that the diminished antimicrobial activity of vasoactive intestinal peptide at physiological salt was regained when LL-37 was added. No study has administered the two peptides together, or against each other, in any living system.
The 10 studies that tested both
- 01In vitro2011
Additive effects of orexin B and vasoactive intestinal polypeptide on LL-37-mediated antimicrobial activities
Ohta K, et al. · Journal of Neuroimmunology · bactericidal assays of orexin B and vasoactive intestinal peptide alone and combined with cationic antimicrobial peptides including LL-37, against Escherichia coli, Pseudomonas aeruginosa, Streptococcus mutans and Staphylococcus aureus, at low and physiological (150 mM) sodium chloride concentrations
Bactericidal activity of vasoactive intestinal peptide alone was detected at low sodium chloride concentration and was attenuated at the physiological concentration of 150 mM. The attenuated activity of both vasoactive intestinal peptide and orexin B at 150 mM sodium chloride was regained when LL-37 was added. The authors concluded that the two neuropeptides appear to mediate bactericidal effects in concert with LL-37 in the physiological context of mucosal tissue.
- 02Review2024
Antimicrobial neuropeptides and their therapeutic potential in vertebrate brain infectious disease
Li X, et al. · Frontiers in Immunology · systematic narrative review of twelve neuropeptides with reported antimicrobial activity, covering structure, potency and mechanism
The review classified LL-37 among the alpha-helical antimicrobial peptides and gave vasoactive intestinal peptide its own section, reporting minimum inhibitory concentrations against Escherichia coli, Pseudomonas aeruginosa and Candida albicans. It restated that the diminished antimicrobial activity of vasoactive intestinal peptide at physiological sodium chloride can be restored by adding LL-37, and noted the same enhancement for orexin B, attributed to the interaction between cationic LL-37 and the amphiphilic neuropeptide facilitating binding to bacterial membranes.
- 03Review2015
The Origin, Expression, Function and Future Research Focus of a G Protein-coupled Receptor, Mas-related Gene X2 (MrgX2)
Wu H, et al. · Progress in Histochemistry and Cytochemistry · narrative review of the origin, expression and function of the human MrgX2 receptor
The review listed vasoactive intestinal peptide and LL-37 together among the peptides that interact with MrgX2, alongside substance P, cortistatin, proadrenomedullin N-terminal peptide, PMX-53 and beta-defensins. It described MrgX2 as expressed on small sensory ganglion neurons and mast cells and linked to nociception, adrenal secretion, mast-cell degranulation and antimicrobial activity. Neither peptide was administered; the paper documents a shared receptor rather than comparative activity.
- 04Review2026
Mas-Related G-Protein-Coupled Receptors: Emerging Roles in Neuropathic Pain
García-Domínguez M · Biomolecules · narrative review of Mas-related G-protein-coupled receptors in nociceptive signalling and neuroimmune interaction
The review grouped LL-37 with beta-defensins as host-defence and antimicrobial peptide agonists of Mas-related receptors, and listed vasoactive intestinal peptide among the cationic amphipathic peptides detected by MRGPRX2 on skin and tissue-resident mast cells. It described that receptor as a hub for IgE-independent mast-cell activation integrating neural, epithelial and microbial signals. The two peptides were catalogued as ligands of the same receptor without any comparative experiment.
- 05Review2025
Mutations of MRGPRX2, drug sensitivity, and genetic markers related to disease
Ratnayake SH, et al. · The Journal of Allergy and Clinical Immunology: Global · narrative review of MRGPRX2 genetic variation, ligand pharmacology and drug hypersensitivity
The review tabulated vasoactive intestinal peptide and LL-37 together in its list of naturally occurring MRGPRX2 agonists, alongside cortistatin-14, oxytocin, neuropeptide FF, proadrenomedullin N-terminal peptide, somatostatin, substance P, mastoparan, pituitary adenylate cyclase-activating polypeptide and beta-defensins. It reported that MRGPRX2 activation is the mechanism by which beta-defensins and cathelicidin LL-37 induce mast-cell degranulation, and described vasoactive intestinal peptide among the basic peptide secretagogues recognised by the same receptor.
- 06Review2023
Therapeutic Peptides for Treatment of Lung Diseases: Infection, Fibrosis, and Cancer
Li S, et al. · International Journal of Molecular Sciences · narrative review of therapeutic peptides in acute lung injury, pulmonary fibrosis and lung cancer, with a tabulated sequence and mechanism list
The review listed the sequences of both peptides in one table of therapeutic peptides for lung disease and placed them in the same schematic of agents acting on nuclear factor-kappa B signalling. LL-37 and its shortened analogue were reported to reduce inflammatory responses and lung injury and to prevent neutrophil infiltration in lipopolysaccharide-induced acute lung injury, while vasoactive intestinal peptide was reported to alleviate lipopolysaccharide-induced lung injury in mice by inhibiting NLRP3 inflammasome activation. The two were reviewed in adjacent mechanism sections rather than compared.
- 07Review2021
Regulatory Peptides in Asthma
Kaczyńska K, et al. · International Journal of Molecular Sciences · narrative review of regulatory peptides implicated in airway inflammation, obstruction and hyperresponsiveness
The review gave vasoactive intestinal peptide its own section as a peptide messenger involved in smooth muscle relaxation, hormone secretion and immune regulation in the airway, and covered LL-37 separately in the antimicrobial peptide section, describing its induction by pathogens, skin damage and vitamin D3 and its roles in wound healing, angiogenesis, apoptosis and immunomodulation. It noted that the reported impact of LL-37 on allergic asthma is not consistent across studies.
- 08Review2023
Effects of Neuropeptides on Dendritic Cells in the Pathogenesis of Psoriasis
Zhang J, et al. · Journal of Inflammation Research · narrative review of neuropeptide effects on dendritic cells in psoriasis pathogenesis
The review described vasoactive intestinal peptide, calcitonin gene-related peptide and substance P as neuropeptides acting on dendritic cells to alter interleukin-12 and interleukin-23 secretion and downstream T helper 1, 17 and 22 responses. In the same pathogenic scheme it described LL-37 forming complexes with self-nucleotides released by damaged keratinocytes, which stimulate plasmacytoid dendritic cells to produce type I interferons and drive myeloid dendritic cell maturation. The two peptides appear on opposite arms of one disease model.
- 09Review2022
The Trinity of Skin: Skin Homeostasis as a Neuro-Endocrine-Immune Organ
Jin R, et al. · Life (Basel) · narrative review of the skin as an integrated neuro-endocrine-immune organ
The review described vasoactive intestinal peptide among the vasoactive neuropeptides released when transient receptor potential channels on sensory nerves are activated, producing increased cutaneous blood flow and telangiectasia. Separately it described cathelicidin cleavage by kallikrein 5 into its active LL-37 form, causing leukocyte chemotaxis, nuclear factor-kappa B activation and angiogenesis, and linked that pathway to the morphological changes of rosacea. Both were placed within one neuro-immune model of skin inflammation.
- 10Review2025
Beyond the classic players: Mas-related G protein-coupled receptor member X2 role in pruritus and skin diseases
Kumar M, et al. · Journal of the European Academy of Dermatology and Venereology · narrative review of MRGPRX2 ligands, signalling and involvement in pruritus and inflammatory skin disease
The review tabulated LL-37 and vasoactive intestinal peptide together among endogenous MRGPRX2 agonists and their cellular sources. It distinguished their signalling behaviour, reporting that substance P activates both G protein and beta-arrestin pathways as a balanced agonist while cathelicidin LL-37 activates G proteins without beta-arrestin as a biased agonist, and cited higher skin reactivity to vasoactive intestinal peptide in chronic spontaneous urticaria as evidence for MRGPRX2 involvement.
Side by side.
| VIP | LL-37 | |
|---|---|---|
| Evidence maturity | Clinical | Early clinical |
| Studies cited here | 15 | 17 |
| Published 2023 or later | 9 | 13 |
| Newest paper | 2026 | 2026 |
| Sequence and origin | A 28-amino-acid neuropeptide of the secretin-glucagon family, released by enteric, autonomic and central neurons, with the synthetic form marketed and studied as aviptadil. | A 37-residue amphipathic alpha-helical peptide, the sole human cathelicidin, cleaved from the hCAP18 precursor encoded by the CAMP gene and expressed by neutrophils, monocytes and epithelial cells. |
| Mechanism as described in the literature | Signals through the class B G protein-coupled receptors VPAC1 and VPAC2 with cyclic AMP as the principal second messenger, producing pulmonary vasodilation, surfactant regulation, suppression of pro-inflammatory cytokine release and regulatory T cell induction, and synchronising suprachiasmatic pacemaker neurons. | Permeabilises microbial membranes directly, neutralises lipopolysaccharide, and chemoattracts neutrophils, monocytes and T cells through FPR2/FPRL1, with CAMP gene transcription induced by 1,25-dihydroxyvitamin D3. Both peptides are also documented ligands of the mast-cell receptor MRGPRX2. |
| Size of the evidence base | Fifteen verified studies in this library, including six human clinical studies and one systematic review, spread across respiratory failure, sarcoidosis, erectile dysfunction and circadian biology. | Seventeen verified studies in this library, including five human clinical studies, five in vitro and four animal in vivo reports, concentrated on antimicrobial activity, wound healing and inflammatory disease. |
| Best-characterised finding | Reduction of tumour necrosis factor-alpha production by bronchoalveolar lavage cells and an increase in bronchoalveolar regulatory T cells after inhaled administration in sarcoidosis, the first demonstration of an immunoregulatory effect of the peptide in humans. | Inhibition of biofilm formation and disruption of pre-grown Pseudomonas aeruginosa biofilms at concentrations far below the minimum inhibitory concentration, through reduced attachment, stimulated twitching motility and downregulated quorum sensing. |
| Human data | Multiple randomised controlled trials of intravenous and inhaled aviptadil. The largest, TESICO, found no significant clinical benefit in COVID-19-associated hypoxaemic respiratory failure, and a 2025 systematic review of ARDS trials reported a pooled survival odds ratio of 1.01. An aviptadil-phentolamine intracavernosal combination is an established second-line agent in erectile dysfunction practice. | Controlled trials by topical and oral routes only. The phase IIb HEAL LL-37 venous leg ulcer trial was negative on its primary analysis, a diabetic foot ulcer trial improved a granulation index without reducing bacterial colonisation or inflammatory cytokines, and an oral recombinant formulation shortened viral clearance time in a COVID-19 trial. No systemic or injectable human data exist. |
| Evidence maturity | Clinical. Adequately powered randomised trials have been completed, and their principal results were negative for the respiratory indication that drove most of the recent development. | Early clinical. Controlled trials exist but are few, small and route-restricted, and no LL-37 product has been approved in any jurisdiction. |
| Recency of primary research | Active but reorienting. The 2023 and 2025 publications are largely negative trial results and their meta-analysis, alongside continuing receptor pharmacology and circadian work published in 2026. | Highly active, with thirteen of the seventeen studies in this library published in 2023 or later, spanning atherosclerosis biomarkers, bacterial evasion, neutrophil extracellular traps and antiviral mechanism. |
| Basis of most marketing claims | Extrapolation from acute-care aviptadil trials and from case series into chronic inflammatory response protocols, a use for which no randomised controlled trial has been published. | Extrapolation from in vitro antimicrobial and antibiofilm data to injectable use in humans, a route with no published clinical data, while the peptide's documented pro-inflammatory role in rosacea, psoriasis and atherosclerosis is generally omitted. |
And what it does not.
One direct comparison exists, and it is a bacterial killing assay. Vasoactive intestinal peptide showed bactericidal activity at low salt that fell away at physiological salt concentration, and adding LL-37 restored it. That describes a complementary interaction in a test tube against four bacterial species; it is not a ranking, it involved no cells, animals or people, and nothing has followed it up in a living system in the fifteen years since. Away from that experiment the two literatures answer different questions. Vasoactive intestinal peptide has the more mature clinical record, with adequately powered randomised trials of aviptadil completed, but its largest trial was negative and meta-analysis of the randomised ARDS evidence shows no survival benefit. LL-37 has the larger and faster-moving mechanistic literature and clear antimicrobial biology, but its controlled human evidence is confined to topical and oral formulations and the largest of those trials failed its primary analysis. Neither peptide has published human evidence for the systemic immune-support use that prompts the comparison.
Common questions.
- What exactly did the study that tested both peptides find?
It measured bacterial killing. Vasoactive intestinal peptide killed Escherichia coli, Pseudomonas aeruginosa, Streptococcus mutans and Staphylococcus aureus at low sodium chloride concentration, but that activity was attenuated at the physiological concentration of 150 mM. When LL-37 was added, the attenuated activity returned. The authors framed the result as the two peptides acting in concert in the physiological environment of mucosal tissue, not as one outperforming the other, and the work was carried out entirely in bactericidal assays.
- Does that assay result support combining the two peptides in humans?
No published work extends it that far. The experiment was conducted in bacterial suspensions at controlled salt concentrations, with no cells, tissue, animal or human component, and no follow-up study has administered the two peptides together in any living system. Salt-dependent loss of antimicrobial activity is a well-documented laboratory artefact for cationic peptides generally, and how it translates to a mucosal surface in a person is not established. The finding is a mechanistic observation about complementarity, not clinical evidence.
- Why do both peptides appear together in mast-cell receptor reviews?
Because both are documented ligands of MRGPRX2, a G protein-coupled receptor on skin and tissue-resident mast cells that mediates IgE-independent degranulation. Reviews of that receptor list vasoactive intestinal peptide and LL-37 side by side with substance P, cortistatin, proadrenomedullin N-terminal peptide and beta-defensins. One review distinguished their signalling, reporting that LL-37 acts as a biased agonist engaging G proteins without beta-arrestin. Sharing a receptor is not evidence that the peptides are interchangeable or that either was tested against the other.
- Which peptide has the more mature clinical evidence?
Vasoactive intestinal peptide, in the sense that adequately powered randomised trials have actually been completed for its synthetic form aviptadil. That maturity cuts both ways: the largest trial, TESICO, found no significant clinical benefit in COVID-19-associated hypoxaemic respiratory failure, and a 2025 systematic review of ARDS trials reported a pooled survival odds ratio of 1.01. LL-37's controlled trials are fewer, smaller and limited to topical and oral formulations, so its evidence base has neither confirmed nor excluded an effect at the same level of rigour.
- Is there any research comparing the two in inflammatory disease rather than infection?
Not as a comparison. Several reviews place them in the same disease model on opposite arms: in psoriasis, vasoactive intestinal peptide is described as acting on dendritic cells to alter interleukin-12 and interleukin-23 secretion while LL-37 forms complexes with self-nucleotides that stimulate plasmacytoid dendritic cells to release type I interferons. In lung disease reviews both appear in one table of therapeutic peptides acting on nuclear factor-kappa B signalling. None of these publications ran an experiment testing one against the other.
For research purposes only. Not for human consumption, diagnosis, treatment, or prevention of any condition. Nothing on this page is medical advice, and no comparison here should be read as a recommendation of either compound.