Interleukin-6 as a multifunctional regulator: Inflammation, immune response, and fibrosis

Abstract

Interleukin 6 (IL-6) is a 184-amino acid protein cytokine that is produced by many types of cells and is expressed during states of cellular stress, such as inflammation, infection, wound sites, and cancer. IL-6 levels may increase several thousand-fold in these states and may help to coordinate the response to dysregulation of tissue homeostasis. IL-6 acts through a membrane-bound IL-6 receptor (mIL-6R), which, together with a second receptor, glycoprotein 130 (gp130), leads to the initiation of intracellular signaling (classic signaling). Given that IL-6R is expressed on only a few types of cells, though all cells express gp130, direct stimulation by IL-6 is limited to cells that express mIL-6R. However, IL-6R is also produced as a soluble, secreted protein that, together with IL-6, can stimulate all gp130-expressing cells by a process termed IL-6 trans-signaling. IL-6 trans-signaling can be blocked without affecting IL-6 classic signaling through mIL-6R. IL-6 has major effects on the adaptive and innate immune system and on mesenchymal and stromal responses during inflammation. It promotes the development of pathogenic T-helper 17 T cells and the maturation of B lymphocytes. Many innate immune cells, neutrophils, and monocytes/macrophages produce and respond to IL-6, resulting in autocrine feedback loops that amplify inflammation. IL-6 has been implicated in the pathogenesis of fibrotic diseases in which IL-6 trans-signaling has been shown to stimulate the proliferation of fibroblasts and the release of procollagen and fibronectin.