1,25OH-Vitamin D3 and IL-17 Inhibition Modulate Pro-Fibrotic Cytokines Production in Peripheral Blood Mononuclear Cells of Patients with Systemic Sclerosis

Addolorata Corrado^*✉, Cinzia Rotondo^*, Eliana Rita Sanpaolo, Alberto Altomare, Nicola Maruotti, Daniela Cici, Francesco Paolo Cantatore

Rheumatology Clinic - Department of Medical and Surgical Sciences, University of Foggia, Foggia- Italy
*These authors contributed equally to this work.

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Citation:
Corrado A, Rotondo C, Sanpaolo ER, Altomare A, Maruotti N, Cici D, Cantatore FP. 1,25OH-Vitamin D3 and IL-17 Inhibition Modulate Pro-Fibrotic Cytokines Production in Peripheral Blood Mononuclear Cells of Patients with Systemic Sclerosis. Int J Med Sci 2022; 19(5):867-877. doi:10.7150/ijms.70984. Available from https://www.medsci.org/v19p0867.htm

Abstract

Objectives: IL-17 modulates the synthesis of several molecules involved in the pathogenesis of Systemic Sclerosis (SSc). Vitamin D (1,25(OH)₂D3) shows anti-fibrotic properties and it is able to affect the IL-17 production in several experimental conditions.

The aim of this study is to assess the production of IL-17A and pro-fibrotic cytokines in peripheral blood mononuclear cells (PBMCs) from subjects with SSc in basal conditions and after treatment with 1,25(OH)2D3 and IL-17A neutralizing antibodies.

Methods: The production of IL-17A and pro-fibrotic cytokines (TGFβ, CTGF and FGF2) in PBMCs obtained from 51 SSc patients and 31 healthy subjects was assessed both in basal conditions and in presence of anti-IL17A antibodies and several concentrations of 1,25(OH)₂D3. The association of cytokines production with clinical disease characteristics and the in vitro effect of 1,25(OH)₂D3 and IL-17A inhibition were assessed.

Results: PBMCs from SSc subjects produced higher amount IL-17A, TGFβ, CTGF and FGF2 compared to healthy controls. IL17, TGFβ, CTGF and FGF2 levels were higher in SSc patients with interstitial lung disease and digital ulcers, whereas IL-17A production was lower in patients with PAH. IL- 17A inhibition reduced the production of FGF2, whereas enhanced the synthesis of TGFβ and CTGF. 1,25(OH)₂D3 decreased the production of IL17A and pro-fibrotic cytokines in a dose- dependent manner.

Conclusions: IL-17A is involved in the regulation of fibrogenesis in SSc, and could represent an intriguing potential therapeutic target, even if its role remains controversial. 1,25(OH)₂D3 inhibits both IL-17A and pro-fibrotic cytokines, confirming its potential anti-fibrotic effect.

Keywords: Systemic Sclerosis, T-lymphocytes, Interleukins, Fibrosis