1. Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines 
Masaaki Murakami, Daisuke Kamimura, Toshio Hirano 
Immunity 
Volume 50, Issue 4, Pages (April 2019)
DOI: /j.immuni
Copyright © 2019 Elsevier Inc. Terms and Conditions

2. Figure 1 Timeline of Key Events in Research on IL-6 Family Cytokines
The timeline of the discovery of IL-6 family cytokines, their receptors, major intracellular signaling molecules, and the approved therapeutics targeting the members of this family since the molecular cloning of IL-6 in 1986 is shown. Ligands, receptors, intracellular signaling molecules, and therapeutics are color coded in green, brown, purple, and red, respectively. Key events in the history of IL-6 family cytokines are shown below the timeline.
Immunity  , DOI: ( /j.immuni )
Copyright © 2019 Elsevier Inc. Terms and Conditions

3. Figure 2 Receptors of IL-6 Family Cytokines
(A) The signal transducer gp130 is shared by all ten family members. IL-6 and IL-11 have the ligand binding receptor subunits IL-6Rα and IL-11Rα, respectively, to transduce intracellular signaling through gp130. OSM binds OSMRβ and gp130 with high affinity, and LIFRβ and gp130 also mediate OSM-induced signal transduction. LIF and CT-1 utilize gp130 and LIFRβ as the signal-transmitting receptor complexes. A classical CNTF receptor is composed of tripartite complexes including CNTFRα, LIFRβ, and gp130. CNTF also uses a receptor combination of IL-6Rα, LIFRβ, and gp130. Like CNTF, the compound cytokine CLCF1-CRLF1 also signals through CNTFRα, LIFRβ, and gp130. IL-27, composed of IL-27 p28 and EBI3, acts via gp130 and WSX-1. It is also known that IL-27 p28 binds to CRLF1 and induces signaling through IL-6Rα, WSX-1, and gp130. IL-35, which consists of EBI3 and IL-12 alpha/p35, uses three possible receptor pairs of IL-12Rβ2 and gp130. IL-39, which comprises IL-23p19 and EBI3, utilizes IL-23R and gp130 for signal transduction.
(B) sIL-6Rα is generated mainly by proteolysis and to a minor extent by alternative splicing in humans. Generation of sIL-11Rα is mediated by proteolysis but not by alternative splicing. The glycosylphosphatidylinositol (GPI) anchor of CNTFRα is cleaved by a phospholipase to generate sCNTFRα. These solubilized forms of cytokine receptors associate with their ligands and then signal in cells that express only gp130 or a receptor pair of gp130 and LIFRβ.
Immunity  , DOI: ( /j.immuni )
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4. Figure 3 Signal Transduction of IL-6
(A) Sites I and II engage IL-6Rα and gp130, respectively. Site III mediates the engagement of two of the trimetric structures, forming a productive signaling complex. D1 represents the immunoglobulin-like domain. D2 and D3 are cytokine-binding homology regions. A magnified image within the circle of the broken line in (C) is shown.
(B) IL-6 binding induces a hexameric complex composed of two molecules each of IL-6, IL-6Rα, and gp130. JAKs are activated by auto- and/or transphosphorylation upon ligand binding via the homodimerization of gp130. The phosphorylation of tyrosine 759 is involved in the gp130-mediated ERK-MAPK pathway via SHP2 and GAB adaptor molecules and is essential for the SOCS3-mediated negative-feedback loop. The distal four tyrosine residues of gp130 (Y767, Y824, Y905, and Y915) form a YXXQ motif, which is required for STAT3 activation. The YAP-Notch pathway triggered by Yes plays a role in the regeneration capacity of injured intestinal epithelium independently of STAT3 activity. Activation of these pathways leads to induction of target mRNAs. TRAF is associated with gp130 and inhibits the STAT3 signaling pathway. All amino acid positions are of human gp130. An immunoglobulin (Ig)-like domain, a four-cysteine motif, and a WSXWS motif are conserved in the extracellular regions of gp130 and IL-6Rα. The JAK binding sites Box1 and Box2 exist in the intracellular region of gp130.
(C) There are three modes of gp130 engagement: classic signaling mode (a magnified image within the circle of broken line is shown in A), trans-signaling mode, and trans-presentation mode. In classic signaling mode, IL-6 binds to IL-6Rα and then associates with gp130 expressed on the same cell’s surface (left). Trans-signaling mode utilizes sIL-6Rα to make IL-6-sIL-6Rα complexes, which act even on IL-6Rα−gp130+ cells (center). In trans-presentation mode, IL-6 bound to IL-6Rα expressed on one type of cells induces intracellular signaling from gp130 expressed on another cell type (right).
Immunity  , DOI: ( /j.immuni )
Copyright © 2019 Elsevier Inc. Terms and Conditions