Prenylated quinolinecarboxylic acid compound-18 prevents sensory nerve fiber outgrowth through inhibition of the interleukin-31 pathway

Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2...

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Bibliographic Details
Published in:PloS one 2021-02, Vol.16 (2), p.e0246630-e0246630
Main Authors: Ogura, Masato, Endo, Kumiko, Suzuki, Toshiyuki, Homma, Yoshimi
Format: Article
Language:English
Subjects:
Atopic dermatitis
Atopy
Attenuation
Biology and Life Sciences
Carboxylic acids
Chemical compounds
Cytokines
Dermatitis
Eczema
Genetic aspects
Growth
Health aspects
Interleukins
Laboratories
Medicine
Medicine and Health Sciences
Nerves
Nervous system
Neuroblastoma
Neurofibrils
Pharmacology
Polyclonal antibodies
Prevention
Proteins
Pruritus
Quality of life
Research and Analysis Methods
Scratching
Scratching behavior
Sensory neurons
Sleep
Social Sciences
Spectrum analysis
Transgenic mice
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Summary:Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2 (PAK2) and improves skin lesions in Nc/Nga mice as an AD model. In the present study, we investigate the effect of PQA-18 on sensory nerves in lesional skin. PQA-18 alleviates cutaneous nerve fiber density in the skin of Nc/Nga mice. PQA-18 also inhibits IL-31-induced sensory nerve fiber outgrowth in dorsal root ganglion cultures. Signaling analysis reveals that PQA-18 suppresses phosphorylation of PAK2, Janus kinase 2, and signal transducer and activator of transcription 3 (STAT3), activated by IL-31 receptor (IL-31R), resulting in inhibition of neurite outgrowth in Neuro2A cells. Gene silencing analysis for PAK2 confirms the requirement for STAT3 phosphorylation and neurite outgrowth elicited by IL-31R activation. LC/MS/MS analysis reveals that PQA-18 prevents the formation of PAK2 activation complexes induced by IL-31R activation. These results suggest that PQA-18 inhibits the IL-31 pathway through suppressing PAK2 activity, which suppresses sensory nerve outgrowth. PQA-18 may be a valuable lead for the development of a novel drug for pruritus of AD.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0246630