Neural activities of IL‐6‐type cytokines often depend on soluble cytokine receptors

Abstract

Cytokines of the interleukin-6 (IL-6) family participate in regulatory and inflammatory processes within the nervous system. IL-6, ciliary neurotrophic factor (CNTF) and IL-11 act via specific membrane receptors which, together with their ligands, associate with signal-transducing receptor subunits thereby initiating cytoplasmic signalling. Cells which only express signal-transducing receptor subunits but no ligand binding subunits for IL-6, CNTF and IL-11 are refractory to these cytokines. An unusual feature of the IL-6 cytokine family is that the soluble forms of the ligand binding receptor subunits generated by one cell type in complex with their ligands can directly stimulate the signal-transducing receptor subunits on different cell types which lack ligand binding receptor subunits. This process has been named transsignalling. This article focuses on the importance of transsignalling events in neuronal differentiation and survival responses.

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

“…Because IL-1␤ and TNF␣ share a number of biological properties, common signaling may be assumed that may involve receptor-associated kinases. This would be in line with a pronounced sensitization of heat-activated ion channels by phosphorylation (Cesare and McNaughton, 1996;März et al, 1999).…”

“…The additional presence of soluble IL-6 receptor is required, and this may represent dual regulation of IL-6 signaling by the cytokine and its receptor. From other models it is known that neural activities of IL-6-like cytokines often depend on soluble receptor (März et al, 1999). A potential role for IL-6 in the inflammatory heat hyperalgesia is further supported by a recent report of a reduced heat sensitivity in IL-6 null mutant mice in the hot plate test (Zhong et al, 1999).…”

Expression of Pancreatitis-Associated Protein after Traumatic Brain Injury: A Mechanism Potentially Contributing to Neuroprotection in Human Brain

“…The principle of trans-signaling via sIL-6R enlarges the spectrum of IL-6 target cells, among them rat sympathetic and DRG neurons (Jones et al 2005;Rose-John et al 2007). From previous studies in our laboratory, it is known that rat sympathetic neurons contain only a marginal number of membrane-bound IL-6 receptors and strongly respond to IL-6 via trans-signaling (März et al 1998(März et al , 1999. In vivo, plasma levels of sIL-6R in healthy individuals were found to be in the range of about 25-35 ng/ml and elevated levels associated with numerous inflammatory disease states such as Crohn's disease, rheumatoid arthritis (RA), juvenile RA, and osteoarthritis (Rose-John et al 2007).…”

The Complex of Ciliary Neurotrophic Factor-Ciliary Neurotrophic Factor Receptor α Up-Regulates Connexin43 and Intercellular Coupling in Astrocytes via the Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription Pathway

“…The glycosyl phosphatidylinositol linkage of CNTFR␣ to the cell membrane can be cleaved by phospholipases releasing CNTFR␣ to act as a soluble protein (Taga et al, 1989). Although most soluble receptors for cytokines and growth factors act antagonistically with their membrane-bound counterparts, soluble CNTFR␣ retains its ability to bind CNTF and act as an agonistic autocrine or paracrine factor (Marz et al, 1999). The heterodimer of CNTF and soluble CNTFR␣ (hereinafter termed "Complex") can trans-signal cells, independent of endogenous CNTFR␣ expression, by binding with the required ␤ subunits glycoprotein 130 (gp130) and leukemia inhibitory factor receptor ␤ (LIFR␤) (Davis et al, 1993a;Rose-John and Heinrich, 1994;Stahl et al, 1994).…”