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Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide ?-endorphin, via STAT3/calcium axis in atopic dermatitis.

ABSTRACT: Itch is the cardinal symptom of atopic dermatitis (AD). ?-Endorphin, a neuropeptide, is increased in both AD skin and sera. Interleukin (IL)-31, an itch-relevant cytokine, activates IL-31 receptors in keratinocytes. However, how IL-31 and ?-endorphin interact in AD skin remains elusive.To investigate the mechanistic interaction of IL-31 and ?-endorphin in AD.This was a prospective cross-sectional study. We recruited adult patients with AD and controls according to Hanifin's AD criteria. Serum levels of IL-31 and ?-endorphin were measured by enzyme-linked immunosorbent assay. Expressions of IL-31 receptor A (IL-31RA) and ?-endorphin in the skin were assessed by immunohistochemistry. Their expression in the skin and blood was compared and correlated in patients with AD and in controls. We also treated primary keratinocytes with IL-31 and measured calcium influx, ?-endorphin production and signalling pathways to define their mechanistic interactions.?-Endorphin was increased in the supernatant from IL-31-treated keratinocytes. IL-31 receptor activation resulted in calcium influx and STAT3 activation; pretreatment with STAT3 inhibitor stopped the increase of ?-endorphin. Notably, either replacement of extracellular calcium or treatment with 2-aminoethoxydiphenyl borate, an inhibitor for the store-operated channel, blocked STAT3 activation. We found higher levels of blood ?-endorphin and IL-31, which were significantly correlated, in patients with AD. Moreover, IL-31RA and ?-endorphin were increased and colocalized both in AD human skin and TPA-painted mouse skin.IL-31 receptor activation in keratinocytes induces calcium influx and STAT3-dependent production of ?-endorphin. These results might contribute to an understanding of the regulatory mechanisms underlying peripheral itch.

SUBMITTER: Lee CH

PROVIDER: S-EPMC3482403 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide β-endorphin, via STAT3/calcium axis in atopic dermatitis.

Lee C-H CH Hong C-H CH Yu W-T WT Chuang H-Y HY Huang S-K SK Chen G-S GS Yoshioka T T Sakata M M Liao W-T WT Ko Y-C YC Yu H-S HS

The British journal of dermatology 20121001 4

<h4>Background</h4>Itch is the cardinal symptom of atopic dermatitis (AD). β-Endorphin, a neuropeptide, is increased in both AD skin and sera. Interleukin (IL)-31, an itch-relevant cytokine, activates IL-31 receptors in keratinocytes. However, how IL-31 and β-endorphin interact in AD skin remains elusive.<h4>Objectives</h4>To investigate the mechanistic interaction of IL-31 and β-endorphin in AD.<h4>Methods</h4>This was a prospective cross-sectional study. We recruited adult patients with AD and ...[more]

PMID: 22578170

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Project description:BackgroundPatients with atopic dermatitis (AD) exhibit heterogeneous clinical phenotypes, reflecting different combinations of itch and lesional severity. AD with severe itch but clear-moderate lesions, also known as itch-dominant AD, is a common clinical phenotype.ObjectivesTo evaluate abrocitinib efficacy in patients with moderate-to-severe AD who have itch-dominant AD.MethodsThis post hoc analysis includes pooled data from clinical trials of patients with moderate-to-severe AD receiving abrocitinib (100 or 200 mg) as monotherapy (phase 2b; phase 3 JADE MONO-1 and JADE MONO-2) or in combination with topical therapy (phase 3 JADE COMPARE). Data from the ongoing long-term JADE EXTEND trial (data cutoff April 2020) were also evaluated. Itch-dominant AD was defined as baseline Peak Pruritus Numerical Rating Scale (PP-NRS) score of 7-10 and Investigator's Global Assessment of 0-3 or Eczema Area and Severity Index of 0‒21. Assessments included a ≥4-point improvement in PP-NRS (PP-NRS4), PP-NRS score of 0 (no itch) or 1 (little itch) in patients with PP-NRS score ≥2 at baseline, ≥4-point improvement from baseline in Patient-Oriented Eczema Measure (POEM-4), Patient Global Assessment (PtGA) of clear or almost clear, and Dermatology Life Quality Index (DLQI) score of 0 or 1 (no impact or little impact of AD on quality of life [QoL]).ResultsIn the pooled monotherapy trials, 37% of patients had itch-dominant AD at baseline. As early as Week 2, more patients with itch-dominant AD achieved PP-NRS4 with abrocitinib 100 mg (35%) and abrocitinib 200 mg (57%) versus placebo (7%); 6% and 22% versus 0%, respectively, achieved PP-NRS 0/1. More patients achieved a PtGA of clear/almost clear at Week 12 with abrocitinib 100 mg (28%) and abrocitinib 200 mg (45%) than placebo (9%). Additionally, abrocitinib led to clinically meaningful improvements in POEM and DLQI. Most patients with itch-dominant AD experienced itch improvement over time with abrocitinib monotherapy or with concomitant topical therapy; 86%-87% and 62%-67% of patients had no itch-moderate itch and clear-moderate lesions by weeks 24 and 48, respectively.ConclusionsAbrocitinib is highly efficacious in patients with itch-dominant AD, demonstrating rapid, deep, and sustained improvements in itch and clinically meaningful improvements in patients' QoL.Trial registration numbersNCT02780167; NCT03349060; NCT03575871; NCT03720470; NCT03422822.

Dataset Information

Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide ?-endorphin, via STAT3/calcium axis in atopic dermatitis.

Publications

Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide β-endorphin, via STAT3/calcium axis in atopic dermatitis.

Similar Datasets

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