IL-6 Transmitter Signal Blockade Attenuates Systemic Sclerosis as Simulated in Mice Model

Abstract

Background: Cytokine interleukin (IL)-6 is involved in the development of systemic sclerosis (SSc). IL-6 forms a complex with soluble IL-6 receptor (sIL-6R), which binds to gp130 and initiates the transmitter signal for pro-inflammatory effects. TJ301 (sgp130-Fc or olamkicept) binds to IL-6-sIL-6R complex, reducing IL-6-sIL-6R binding to gp130 and inhibiting the transmitter signal. The aim of this study was to determine whether TJ301 can be used to treat SSc by inhibiting the IL-6 transmitter signal. Methods: Wild-type C57BL/6 mice were randomly distributed into experimental and control groups. Mice were injected subcutaneously with bleomycin (BLM, saline in the control group) for 28 days to induce SSc. Meanwhile, MR16-1, saline and TJ301 (saline in the control group) were separately injected to mice. On day 29, IL-6 and IL6Rα levels of blood, skin and lung tissues histological analysis, and collagen I, CD31 and α-smooth muscle actin (α-SMA) of skin tissue expression were determined. The human foreskin fibroblast (HFF-1) cells and human dermal microvascular endothelial cells (HDMEC) were treated using transforming growth factor (TGF)-β1, with or without TJ301. For HFF-1 cells, cell viability, IL-6 and IL-6Rα levels and collagen I and αSMA expression were determined. For HDMEC, migration rate, IL-6 and IL-6Rα levels, αSMA and CD31 expression and endothelial-to-mesenchymal transition (EndoMT) were detected. Results: Higher concentrations of IL-6 and sIL-6R were found in BLMtreated animals blood. Additionally, their skin and lungs exhibited greater collagen accumulation and myofibroblasts that were positive for α-SMA. Inflammation level, immune cells that entered quantity, and profibrotic genes expression in skin and lung tissues were all reduced when TJ301 was used to block IL-6 transmitter signal. When triggered by TGF-1 in the lab, TJ301 may prevent dermal fibroblast and microvascular endothelial cells from expanding and migrating. Conclusions: Using TJ301 to inhibit the IL-6 transmitter signal may be a novel approach to treat SSc.