Immunomodulating role of the JAKs inhibitor tofacitinib in a mouse model of bleomycin-induced scleroderma.
J Dermatol Sci
; 101(3): 174-184, 2021 Mar.
Article
em En
| MEDLINE
| ID: mdl-33451905
ABSTRACT
BACKGROUND:
Janus kinase (JAK)-signal transducer and activator of transcription (STAT) was hyperactivated in biopsies from patients with systemic sclerosis (SSc) and in several autoimmune disease models. Tofacitinib, a pan-JAK inhibitor, blocks the downstream signaling of multiple cytokines and has exhibited therapeutic efficacy in various autoimmune diseases, although its immunomodulating property in scleroderma is unclear.OBJECTIVE:
To evaluate the effect of tofacitinib on the modulation of cytokine-producing T and B cells, and proinflammatory cells in a mouse model of SSc.METHODS:
Bleomycin (BLM)-induced SSc was generated by intradermal injection of BLM or PBS for control. Mice received intraperitoneal tofacitinib (20 mg/kg) or vehicle 3 times per week from day 0-28. Mice were sacrificed at day 28 after the last BLM/PBS injection.RESULTS:
Tofacitinib administration significantly alleviated fibrosis of the skin and lungs in scleroderma mouse model. Furthermore, tofacitinib suppressed adaptive and innate immune responses by reducing splenocytes, total lymphocytes, CD4+ T helper cells (especially Th2 and Th17 subtypes), IL-6-producing effector B cells, PDCA-1+ dendritic cells in the spleen, and infiltration of F4/80+, CD206+ and CD163+ macrophages in the skin and lungs. Conversely, tofacitinib increased the proportions of splenic regulatory T and B cells. The mRNA expression of extracellular matrix proteins and fibrogenic cytokines was downregulated by tofacitinib in both the skin and lungs.CONCLUSION:
These observations suggest JAK inhibition as a therapeutic approach for the treatment of inflammatory and fibrotic diseases, and highlight the potential of tofacitinib as a promising candidate for treating patients with scleroderma.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Pirimidinas
/
Escleroderma Sistêmico
/
Inibidores de Janus Quinases
Idioma:
En
Revista:
J Dermatol Sci
Assunto da revista:
DERMATOLOGIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão