The Role of IL-6 in Fibrotic Diseases: Molecular and Cellular Mechanisms

Abstract

Fibrosis is a detrimental outcome of most chronic inflammatory disorders and is defined by the buildup of excess extracellular matrix (ECM) components, which eventually leads to organ failure and death. Interleukin 6 (IL-6) is promptly produced by immune cells in response to tissue injuries and has a wide range of effects on cellular processes such as acute responses, hematopoiesis, and immune reactions. Furthermore, high levels of IL-6 have been found in a variety of chronic inflammatory disorders characterized by fibrosis, and this factor plays a significant role in fibrosis in various organs via Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) activation. Here, we review what is known about the role of IL-6 in fibrosis and why targeting IL-6 for fibrotic disease treatment makes sense.

Keywords: Interleukin 6; JAK; STAT3; fibrosis.

Fig 1

Two different modes of IL‑6 signaling. IL-6 can bind to both mIL‑6R (classic signaling) and sIL-6R (trans-signaling). After homodimerization of the signal-transducing receptor subunit gp130 on the plasma membrane, the two signaling pathways converge, triggering the intracellular JAK/STAT and MAPK signaling cascades. SOCS is the product of JAK/STAT3 signaling pathway activation and is also a protein associated with the negative-feedback reaction that leads to the inhibition of this signaling pathway.

Fig 2

Effect and mechanism of IL-6 on organ fibrosis. Chronic inflammation is caused by injury (pathogens, toxins, mechanical injury), and monocytes, macrophages, B cells and fibroblasts release IL-6 at the wound site. IL-6 promotes the transformation of fibroblasts into myofibroblasts through the JAK/STAT3 signaling pathway.