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Antifibrotic effect of apremilast in systemic sclerosis dermal fibroblasts and bleomycin-induced mouse model
Tomoaki Higuchi1,2, Kae Takagi3, Akiko Tochimoto3
1Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan. higuchi.tomoaki@twmu.ac.jp.
Abstract:
Phosphodiesterase (PDE) 4 inhibitors have been reported to suppress the progression of dermal fibrosis in patients with systemic sclerosis (SSc); however, the precise mechanisms remain to be elucidated. Therefore, we conducted experiments focusing on the antifibrotic and anti-inflammatory effects of apremilast using dermal fibroblasts derived from patients with SSc and an SSc mouse model. Dermal fibroblasts derived from healthy controls and patients with SSc were incubated with apremilast in the presence or absence of 10 ng/ml transforming growth factor (TGF)-β1 for the measurement of intracellular cAMP levels and evaluation of mRNA and protein expression. A bleomycin-induced dermal fibrosis mouse model was used to evaluate the inhibitory effects of apremilast on the progression of dermal fibrosis. Intracellular cAMP levels were significantly reduced in dermal fibroblasts derived from patients with SSc compared with those derived from healthy controls. Apremilast reduced the mRNA expression of profibrotic markers and the protein expression of type I collagen and Cellular Communication Network Factor 2 (CCN2) in dermal fibroblasts. Additionally, apremilast inhibited the progression of dermal fibrosis in mice, partly by acting on T cells. These results suggest that apremilast may be a potential candidate for treating dermal fibrosis in SSc.
Insights
Apremilast, a phosphodiesterase 4 inhibitor, reduces dermal fibrosis in systemic sclerosis (SSc) by decreasing profibrotic markers and acting on T cells. This study highlights its potential as an SSc treatment.
Area of Science:
- Immunology
- Dermatology
- Pharmacology
Background:
- Systemic sclerosis (SSc) is characterized by dermal fibrosis, a process potentially modulated by phosphodiesterase (PDE) 4 inhibitors.
- The precise mechanisms by which PDE 4 inhibitors exert antifibrotic effects in SSc remain unclear.
- Apremilast is a known PDE 4 inhibitor with potential therapeutic applications.
Purpose of the Study:
- To investigate the antifibrotic and anti-inflammatory effects of apremilast in systemic sclerosis (SSc).
- To elucidate the mechanisms underlying apremilast's action on dermal fibroblasts and in an SSc mouse model.
Main Methods:
- Dermal fibroblasts from SSc patients and healthy controls were treated with apremilast and transforming growth factor-β1 (TGF-β1).
- Intracellular cAMP levels, mRNA expression of profibrotic markers, and protein expression of type I collagen and CCN2 were measured.
- A bleomycin-induced dermal fibrosis mouse model was used to assess apremilast's in vivo efficacy.
Main Results:
- Dermal fibroblasts from SSc patients exhibited reduced intracellular cAMP levels compared to controls.
- Apremilast treatment decreased mRNA expression of profibrotic markers and protein levels of type I collagen and CCN2 in SSc fibroblasts.
- Apremilast administration inhibited dermal fibrosis progression in the SSc mouse model, partly through effects on T cells.
Conclusions:
- Apremilast demonstrates significant antifibrotic effects in SSc models.
- The drug reduces key profibrotic markers and influences immune cell activity.
- Apremilast shows promise as a potential therapeutic agent for treating dermal fibrosis in systemic sclerosis.
