Updating interleukin-6 classic- and trans-signaling

Abstract

The cytokine interleukin-6 has been identified and cloned among others as B-cell stimulatory factor, hepatocyte stimulating factor, plasmacytoma growth factor, and interferon beta-2. Consequently, it emerged, that IL-6 controls a huge variety of cellular functions, among them induction of the acute phase response in the liver, mediation of inflammation and malignant transformation. In this review, we summarize the so called classical IL-6 signaling, which is mediated by the complex of IL-6, the membrane bound IL-6R and two gp130 molecules, and an alternative pathway called trans-signaling, which apparently contributes to the development of chronic inflammation and cancer. During trans-signaling an agonistic soluble IL-6R is generated, which sensitizes cells lacking the membrane bound IL-6R. Finally, we discuss specific inhibition of IL-6-trans-signaling processes by a naturally occurring soluble form of gp130, demonstrating that this protein may emerge as an important future therapeutic in clinical applications for chronic inflammation.