TGFβ-mediated expression of TGFβ-activating integrins in SSc monocytes: disturbed activation of latent TGFβ?

Arthritis Research & Therapy
A van CaamP M van der Kraan

Abstract

The pathophysiology of systemic sclerosis (SSc) is closely linked to overactive TGFβ signaling. TGFβ is produced and circulates in latent form, making its activation crucial for signaling. This activation can be mediated via integrins. We investigated the balance between active and latent TGFβ in serum of SSc patients and investigated if this correlates with integrin expression on monocytes. A TGFβ/SMAD3- or BMP/SMAD1/5-luciferase reporter construct was expressed in primary human skin fibroblasts. Both acidified and non-acidified sera of ten SSc patients and ten healthy controls were tested on these cells to determine total and active TGFβ and BMP levels respectively. A pan-specific TGFβ1/2/3 neutralizing antibody was used to confirm TGFβ signaling. Monocytes of 20 SSc patients were isolated using CD14+ positive selection, and integrin gene expression was measured using qPCR. Integrin expression was modulated using rhTGFβ1 or a small molecule inhibitor of TGFBR1: SB-505124. SSc sera induced 50% less SMAD3-reporter activity than control sera. Serum acidification increased reporter activity, but a difference between healthy control and SSc serum was no longer observed, indicating that total TGFβ levels were not different. Additio...Continue Reading

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Citations

Aug 1, 2020·Frontiers in Cell and Developmental Biology·Adilson Fonseca TeixeiraHong-Jian Zhu
Feb 12, 2021·Frontiers in Physiology·An-Ran ShenLin-Li Lv
May 27, 2021·Scientific Reports·Julien GuiotRenaud Louis
Jun 29, 2021·Biophysics Reviews·Pearlin Hameed, Geetha Manivasagam

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Methods Mentioned

BETA
PCR
enzyme-linked immunosorbent assays
ELISA

Software Mentioned

GraphPad Prism

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