Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Interleukin-6 Family Cytokines Stefan Rose-John Institute of Biochemistry, Kiel University, Olshausenstrasse 40, Kiel, Germany Correspondence: [email protected] The interleukin (IL)-6 family cytokines is a group of cytokines consisting of IL-6, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotro- phin 1 (CT-1), cardiotrophin-like cytokine (CLC), and IL-27. They are grouped into one family because the receptorcomplex of each cytokine contains two (IL-6 and IL-11) or one molecule (all others cytokines) of the signaling receptor subunit gp130. IL-6 family cytokines have overlapping but also distinct biologic activities and are involved among others in the regula- tion of the hepatic acute phase reaction, in B-cell stimulation, in the regulation of the balance betweenregulatoryandeffectorTcells,inmetabolicregulation,andinmanyneuralfunctions. Blockade of IL-6 family cytokines has been shown to be beneficial in autoimmune diseases, but bacterial infections and metabolic side effects have been observed. Recent advances in cytokine blockade might help to minimize such side effects during therapeutic blockade. ytokines are small (15–20 kDa) and short- bopoietin, leukemia inhibitory factor (LIF), Clived proteins important in autocrine, para- and oncostatin M (OSM). Moreover, all inter- crine, and endocrine signaling. Cytokines coor- ferons and many colony-stimulating factors dinate the development and the activity of the (CSFs) belong to this class of cytokines, which immune system (Gandhi et al. 2016). Many cy- altogether contains far more than 60 members tokines belong to the four a-helical class of me- (Spangler et al. 2015). diators, which share a common up-up–down- Interleukin (IL)-6 family cytokines are de- down topology of the four helices. Furthermore, finedascytokinesthatusethecommonsignaling cytokines are grouped into families according to receptor subunit glycoprotein 130 kDa (gp130). the structure and the specificity and composi- Presently, eight cytokines fulfill this criterion tion of their receptorcomplexes. Cytokines bind although, as will be explained below, the group tomultimeric receptorcomplexesinwhichoften of IL-6 family cytokines is still expanding and one subunit is also found in the receptor com- the definition of gp130-containing complexes plexes for other cytokines (Spangler et al. 2015). needs to be revised (Rose-John et al. 2015). This is a reasonable classification because com- IL-6 family cytokines have been implicated in mon receptor subunits imply similarity or even many functions, including B-cell stimulation and identity in intracellular signal transduction. induction of the hepatic acute phase proteins. The class of four-helical cytokines consists Moreover, metabolic functions and neurotrophic of more than 35 interleukins and many media- functions have been ascribed to this group of tors with trivial names such as growth hor- cytokines. Lately, an IL-6 receptor (IL-6R)-neu- mone, prolactin, leptin, erythropoietin, throm- tralizing monoclonal antibody (tocilizumab) has Editors: Warren J. Leonard, and Robert D. Schreiber Additional Perspectives on Cytokines available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a028415 1 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press S. Rose-John been approved in more than 100 countries for cDNA coding for the human IL-6R (Yamasaki the treatment of autoimmune diseases (Tanaka et al. 1988). The receptor belonged to the im- et al. 2014), and blockade of IL-6 activity was munoglobulin (Ig) superfamily but the cyto- observed to be at least as efficient as the block- plasmic portion lacked a domain with discern- ade of tumor necrosis factor a in patients with ible enzymatic activity, thus failing to provide rheumatoid arthritis (Gabay et al. 2013). any clue regarding the mechanism of signal This review covers the identification and transduction induced by IL-6. Figure 1 shows complementary DNA (cDNA) cloning of IL-6 how IL-6 and IL-6R were seen during these early family cytokines, the identification of their cog- days of the cytokine field when there was no nate receptors, and the recognition that these information on the structure of these molecules. cytokines form a large family of mediators, Because cytokines show very little homology which are involved in the coordination of the at the protein level, it was not clear at the time immune system but also in many other physio- that cytokines share common features and actu- logic functions as well. ally belong to a common protein family. At this time, a seminal article was published by Bazan (1990), who hypothesized that cytokines such as CLONING OF IL-6, IL-6R, AND gp130: growth hormone, prolactin, IL-6, G-CSF, and THE IL-6R COMPLEX erythropoietin belong to the protein family When the cDNA coding for B-cell stimulatory of four-helical cytokines. Bazan stated that factor 2 (BSF-2) was cloned in 1986 by the Ki- lymphokines, interleukins, CSFs, growth hor- shimoto group, the comparison of its protein mones, and interferons, which he collectively sequence with the protein sequences of IL-1, IL- designated as cytokines, display no (or at best 2, IL-4, interferon g (IFN-g), granulocyte mac- fragmentary) similarities in amino acid se- rophage colony-stimulating factor (GM-CSF), quence. All these proteins, however, were pre- and granulocyte colony-stimulating factor (G- dicted or had been shown to be rich in a-helices. CSF) yielded only some faint similarities with Based on the then already-published X-ray G-CSF (Hirano et al. 1986). It became, however, structure of G-CSF (Abdel-Meguid et al. 1987) immediately clear from the cDNA sequence that and the high predicted helical content of growth BSF-2 was identical to several other proteins hormone, prolactin, IL-6, G-CSF, and erythro- with completely different biologic activities (Ta- poietin, Bazan suggested a four-helical tertiary ble 1), indicating that the activity of the newly fold for cytokines, an idea that he also backed by cloned BSF-2 was not restricted to the immune the conserved gene exon/intron boundaries system. In December 1988, a group of 19 leading flanking the helices and by conserved disulfide scientists in the field, including Dr. Kishimoto, bridge patterns (Bazan 1990). Based on his agreed to refer to the protein as IL-6 (The New model, Bazan even detected that the protein to- York Academy of Sciences Conference 1988). pology in the then-published X-ray structure of No structural or functional information IL-2 was incorrect and needed correction (Ba- on IL-6 or the IL-6R complex was available zan 1992). Now we know that all cytokines of the until, in 1988, the Kishimoto group cloned the IL-6 family, but also essentially all other cyto- kines, share the four-helices with an up-up– Table 1. Synonyms of interleukin-6 as evidenced on down-down topology (Fig. 1). It was recognized complementary DNA (cDNA) cloning of B-cell stim- that, instead of showing clear sequence homol- ulatory factor 2 (BSF-2) ogy, cytokines are characterized by a high struc- B-cell stimulatory factor-2 (Hirano et al. 1986) tural homology (Spangler et al. 2015). Such Hepatocyte-stimulating factor (Gauldie et al. 1987) structural homology extends to cytokine recep- Hybridoma-plasmacytoma growth factor tors, which all belong to the Ig superfamily and (Brakenhoff et al. 1987) which contain a cytokine-binding module con- Interferon b2 (Zilberstein et al. 1986) sisting of tandem fibronectin III domains where 26 kDa protein (Haegeman et al. 1986) the amino-terminal domain contains a set of 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a028415 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press IL-6 Family Cytokines ABS NH2 S Ig domain ≈ Site 1 S 90 aa NH2 S COOH S ≈ 250 aa IL-6R S Transmembrane ≈ IL-6 domain 28 aa Cytoplasmic ≈ COOH domain 82 aa CDA-B C-D C-D loop Helix loop Helix Helix loop Helix B-C loop GRH NH2 A B C D COOH PRL NH2 A B C D COOH B A-B loop IL-6 NH2 A B C D COOH D A C G-CSF NH A B C D COOH 2 IL-6 EPO NH A B C D COOH 2 NH COOH 2 Figure 1. Recognition of interleukin-6 (IL-6) as a four-helical cytokine with up-up–down-down topology. (A) IL-6 was functionally characterized by sets of monoclonal antibodies and it was stated that the NH2 terminus and the COOH terminus must be in close proximity in the biologic active IL-6 protein (Brakenhoff et al. 1990). Hypothesized disulfide bridges are indicated in red. (B) When the complementary DNA (cDNA) coding for the IL-6 receptor (IL-6R) was cloned, no details about structure or function were available and only a schematic model of the IL-6R as a member of the immunoglobulin (Ig) superfamily could be envisioned (Hirano et al. 1989). A single hypothesized disulfide bridge is shown in blue. Postulated N-glycosylation sites are shown in green. (C) It was recognized by Bazan (1990) that, although growth hormone (GRH), prolactin (PRL), IL-6, granulocyte colony-stimulating factor (G-CSF), and erythropoietin (EPO) (Bazan 1990) display no (or at best fragmentary) similarities in amino acid sequence, they share exon–intron boundaries at predicted secondary structure elements (red arrowheads) and predicted disulfide bridges. Based on the known three-dimensional structure of G-CSF (Abdel-Meguid et al. 1987), Bazan postulated that GRH, PRL, IL-6, G-CSF,and EPO formed a structurally related family of cytokines.