Targeted inhibition of EPAS1-driven IL-31 production by a small-molecule compound.
J Allergy Clin Immunol
; 148(2): 633-638, 2021 08.
Article
en En
| MEDLINE
| ID: mdl-33819507
ABSTRACT
BACKGROUND:
IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibition of IL-31 production remain unexploited. IL-31 production by TH cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1.OBJECTIVE:
We aimed at developing small-molecule inhibitors that selectively block IL-31 production by TH cells.METHODS:
We generated the reporter cell line that inducibly expressed EPAS1 in the presence of doxycycline to mediate Il31 promoter activation, and we screened 9600 chemical compounds. The selected compounds were further examined by using TH cells from a spontaneous mouse model of AD and TH cells from patients with AD.RESULTS:
We have identified 4-(2-(4-isopropylbenzylidene)hydrazineyl)benzoic acid (IPHBA) as an inhibitor of IL31 induction. Although IPHBA did not affect nonspecific T-cell proliferation, IPHBA inhibited antigen-induced IL-31 production by TH cells from both an AD mouse model and patients with AD without affecting other cytokine production and hypoxic responses. In line with this, itch responses induced by adoptive transfer of IL-31-producing TH cells were attenuated when mice were orally treated with IPHBA. Mechanistically, IPHBA inhibited the association between EPAS1 and SP1, resulting in defective recruitment of both transcription factors to the specific sites of the IL31 promoter. We also determined the structure-activity relationship of IPHBA by synthesizing and analyzing 201 analogous compounds.CONCLUSION:
IPHBA could be a potential drug leading to inhibition of EPAS1-driven IL-31 production.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Regulación de la Expresión Génica
/
Interleucinas
/
Doxiciclina
/
Dermatitis Atópica
/
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Allergy Clin Immunol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Japón