Altered CD4+ T cell and cytokine levels in peripheral blood and skin samples from systemic sclerosis patients and IL-35 in CD4+ T cell growth

Objective This study explored the role of IL-35 in CD4(+) T lymphocyte and human skin fibroblast (HSF) activity and cytokine levels in systemic sclerosis. Methods Blood and skin biopsies were collected from 41 patients and 39 healthy controls to assess CD4(+) T lymphocytes and IL-35-related factors. CD4(+) T lymphocytes were co-cultured with HSFs, recombinant human IL-35 and IL-35 mAb to evaluate the cell viability, activation of CD4(+) T lymphocytes and HSF cells. Results The proportion of blood Th1/Th2 was lower and Th17/Treg was higher in patients than in controls (P < 0.05). IL-35 and IL-17A levels were higher and IFN-gamma, IL-10 and TGF-beta levels were lower in patients than in controls. IL-17A, forkhead box P3, TGF-beta 1 and collagen type I (COL-1) mRNA and phospho (p)-signal transducer and activator of transcription (STAT) 1 and p-STAT4 were higher in skin tissues from patients than in those from controls (P < 0.05). IL-6 levels were higher, whereas IL-10 levels were lower in cell culture supernatants. alpha-Smooth muscle actin (alpha-SMA) and COL-1 proteins and Ki67 positivity were higher in CD4(+) T + HSF cells from patients than in those from controls. Recombinant human IL-35 treatment inhibited proliferation (P < 0.001), but increased IL-10 and decreased IL-17A, alpha-SMA and COL-1 secretion into the conditioned medium of CD4(+) T lymphocytes + HSFs from patients compared with those from controls. IL-35 mAb blocked the effects of IL-35 in CD4(+) T + HSF cells (P < 0.05). Conclusions IL-35 plays an inhibitory role in CD4(+) T lymphocyte proliferation but induces Treg cell differentiation by STAT1 signalling activation, HSF proliferation and collagen expression in systemic sclerosis.

Automated summary

This study investigated the role of IL-35 in the activity of CD4(+) T lymphocytes and human skin fibroblasts (HSFs) as well as cytokine levels in systemic sclerosis. The results showed that IL-35 inhibits the proliferation of CD4(+) T lymphocytes and induces the differentiation of Treg cells through STAT1 signaling activation, while promoting HSF proliferation and collagen expression in systemic sclerosis.