In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease

Abstract

Background: The remarkable mechanisms of storiform fibrosis and the formation of high levels of IgG4 with a pathogenic germinal center (GC) in the inflammatory tissue of IgG4-RD remains unknown and may be responsible for the unsatisfactory therapeutic effect on IgG4-related diseases when using conventional therapy. Objectives: To investigate the mechanisms of interleukin 6 (IL-6) inducing fibroblasts to produce cytokines for pathogenic GC formation in the development of IgG4-related disease (IgG4-RD). Methods: The clinical data and laboratory examinations of 56 patients with IgG4-RD were collected. IL-6 and IL-6R expression in the serum and tissues of patients with IgG4-RD and healthy controls were detected by ELISA, immunohistochemistry, and immunofluorescence. Human aorta adventitial fibroblasts (AAFs) were cultured and stimulated with IL-6/IL-6 receptor (IL-6R). The effect of IL-6/IL-6R on AAFs was determined by Luminex assays. Results: The serum IL-6 and IL-6R levels were elevated in active IgG4-RD patients and IL-6 was positively correlated with the disease activity (e.g., erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and IgG4-RD responder index). IL-6 and IL-6R expression in the tissue lesions of IgG4-related retroperitoneal fibrosis and IgG4-related sialadenitis patients were also significantly higher than that in the normal tissues. In addition, there is a relative abundance of myofibroblasts as well as IgG4 + plasma cells in the tissues of IgG4-related retroperitoneal fibrosis. α-SMA and B cell differentiation cytokines (i.e., B cell activating factor), and α-SMA and T follicular helper (Tfh) cell differentiation cytokines (e.g., IL-7, IL-12, and IL-23) were co-expressed in the local lesions. In vitro, IL-6/IL-6R significantly promoted the production of B cell activating factor, IL-7, IL-12, and IL-23 in AAFs in a dose-dependent manner. This effect was partially blocked by JAK1, JAK2, STAT3, and Akt inhibitors, respectively. Conclusions: In vitro IL-6/IL-6R trans-signaling in fibroblasts releases Tfh and B cell differentiation factors partially via the JAK2/STAT3, JAK1/STAT3, and JAK2/Akt Zongfei et al. IL-6 and Fibroblast Induced IgG4-RD pathways, which may be linked to the pathogenesis of IgG4-RD. This indicated that IL-6 and fibroblasts may be responsible for GC formation and fibrosis in the development of IgG4-RD. Blocking IL-6 with JAK1/2 inhibitors or inhibiting fibroblast proliferation might be beneficial for IgG4-RD treatment.

IL-6 expression helps distinguish Castleman’s disease from IgG4-related disease in the lung

“…Clinicopathologically, increased IL-6 levels were reported in IgG4-RD [ 16 ] and IL-6 was elevated in IgG4-related dacryoadenitis and sialadenitis [ 17 ]. The reason for high IL-6 levels in IgG4-RD is not well understood, but IL-6 is thought to directly promote the development of fibrosis in damaged tissues [ 18 , 19 ].…”

Improved clinical outcomes of tocilizumab versus cyclophosphamide for IgG4-related disease: insights from a prospective IgG4-related disease registry

“…In a recent study, we showed that IL-6 could promote the pathogenesis of IgG4-RD by inducing fibroblasts releasing Tfh and B cell differentiation factors. 8 However, the therapeutic effect of the IL-6R antibody tocilizumab on IgG4-RD has not been reported to date, and the effectiveness of tocilizumab has only been reported in several retroperitoneal fibrosis and chronic periaortitis cases. 21 , 22 Retroperitoneal fibrosis and chronic periaortitis are thought to have overlap with IgG4-RD.…”

“… 6 Therefore, in recent randomized controlled trials (RCTs) conducted in patients with IgG4-RD, attention has been paid to the effectiveness of steroid-sparing agents known as immunosuppressors. 7 – 9 It has been suggested that leflunomide or mycophenolate mofetil (MMF), used in combination with GCs, was superior to GC therapy alone. 7 , 8 A prospective study also indicated that the use of GCs plus cyclophosphamide (CYC) reduced the relapse rate better than did GCs plus MMF.…”

“… 7 – 9 It has been suggested that leflunomide or mycophenolate mofetil (MMF), used in combination with GCs, was superior to GC therapy alone. 7 , 8 A prospective study also indicated that the use of GCs plus cyclophosphamide (CYC) reduced the relapse rate better than did GCs plus MMF. 10 Regarding biological agents, the other type of steroid-sparing agents, in an open-label study in which 30 patients were enrolled, 47% achieved CR with rituximab monotherapy.…”

“…Given that the conventional therapeutic approach for IgG4-RD management is associated with a high recurrence rate, side effects, and difficulty in reducing GC dose, it is important to further explore new therapies based on the pathogenesis of the disease. Our recent study showed that interleukin 6 (IL-6) plays an important role in the pathogenesis of IgG4-RD, 8 that is, IL-6/IL-6R can promote fibroblasts releasing follicular helper T (Tfh) and B cell differentiation factors. Tocilizumab, a humanized IL-6 receptor monoclonal antibody, has been widely used in the management of various autoimmune diseases.…”