IL-6: A New Era for the Treatment of Autoimmune Inflammatory Diseases

Abstract

A series of studies have revealed that IL-6 has pleiotropic activity in various cells and that its deregulated expression is responsible for the development of multiple autoimmune infl ammatory diseases. A humanized antibody against the IL-6 receptor, tocilizumab, has exhibited outstanding therapeutic effi cacy against rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, and other autoimmune infl ammatory diseases, leading to its clinical use for treatment of several diseases. These fi ndings indicate that overproduction of IL-6 is responsible for the pathogenesis of autoimmune infl ammatory diseases, in which an imbalance between Th17 cells and regulatory T cells and autoantibodies play central roles. Recent studies have suggested that IL-6 blockade therapy can rectify these underlying immunological abnormalities in autoimmunity. However, the causes of deregulated IL-6 production in these diseases remain unknown. A novel IL-6-regulating molecule, Arid5a, specifi cally stabilizes IL-6 mRNA and sustains its overproduction; thus, Arid5a plays an important role in promoting infl ammation and autoimmune diseases. Indeed, in Arid5a-knockout mice, experimental autoimmune encephalomyelitis does not develop, and lipopolysaccharide stimulation does not induce elevated expression of IL-6. Arid5a can counteract the destabilizing effect of a regulatory RNase, Regnase-1, on IL-6 mRNA; Regnase-1 knockout mice spontaneously develop various fatal autoimmune diseases. Further analyses of these RNA-binding proteins as well as other regulatory molecules for IL-6 expression are expected to elucidate the molecular mechanisms underlying deregulated synthesis of IL-6, and facilitate investigations of the pathogenesis of specifi c diseases.

Clinically based score predicting cryptogenic NORSE at the early stage of status epilepticus

“…32,33 IL-6 secreted from macrophages is also important mediator of fever and its deregulated expression is responsible for development of a variety of autoimmune inflammatory diseases. 34 The efficacy of tocilizumab, IL-6 receptor antagonist, has also been reported in patients with NORSE. 35 Therefore, elevated CSF levels of proinflammatory cytokines may play an important role in neuroinflammation, leading to development of refractory partial seizures in NORSE or FIRES.…”

M2b macrophage polarization and its roles in diseases

“…IL‐6 binds to its receptor IL‐6R, and this complex then binds to a second membrane protein, glycoprotein 130 (gp130), which dimerizes and initiates intracellular signaling . Promptly and transiently produced in response to infections and tissue injuries, IL‐6 contributes to host defense through the stimulation of acute phase responses, immune reactions, and hematopoiesis . Almost all stromal cells and immune cells are involved in the production of IL‐6 .…”

“…82,83 Promptly and transiently produced in response to infections and tissue injuries, IL-6 contributes to host defense through the stimulation of acute phase responses, immune reactions, and hematopoiesis. 84,85 Almost all stromal cells and immune cells are involved in the production of IL-6. 86,87 It is secreted by monocytes and macrophages after stimulation of TLR ligands.…”

Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review

“…IL-6 in combination with transforming growth factor-beta (TGF)-β preferentially induces differentiation into Th17 cells, whereas IL-6 inhibits TGFβ-induced Treg development. The resultant predominance of Th17 cells over Treg cells may be responsible for the breakdown of immunological tolerance, and may therefore be pathologically involved in the development of AD [110]. Deregulated excessive IL-6 synthesis during this protective process or persistent IL-6 production leads to the development of a severe acute life-threatening complication, the socalled cytokine storm or AD respectively [111].…”