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IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

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IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions cells Review IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions Doreen M. Floss *, Jens M. Moll and Jürgen Scheller Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, D-40225 Düsseldorf, Germany; [email protected] (J.M.M.); [email protected] (J.S.) * Correspondence: doreen.fl[email protected]; Tel.: +49-211-811-1642 Received: 10 September 2020; Accepted: 27 September 2020; Published: 28 September 2020 Abstract: Cytokines of the IL-12 family show structural similarities but have distinct functions in the immune system. Prominent members of this cytokine family are the pro-inflammatory cytokines IL-12 and IL-23. These two cytokines share cytokine subunits and receptor chains but have different functions in autoimmune diseases, cancer and infections. Accordingly, structural knowledge about receptor complex formation is essential for the development of new therapeutic strategies preventing and/or inhibiting cytokine:receptor interaction. In addition, intracellular signaling cascades can be targeted to inhibit cytokine-mediated effects. Single nucleotide polymorphisms can lead to alteration in the amino acid sequence and thereby influencing protein functions or protein–protein interactions. To understand the biology of IL-12 and IL-23 and to establish efficient targeting strategies structural knowledge about cytokines and respective receptors is crucial. A highly efficient therapy might be a combination of different drugs targeting extracellular cytokine:receptor assembly and intracellular signaling pathways. Keywords: IL-12 family cytokines; IL-12; IL-23; signaling; autoimmune diseases 1. Introduction Cytokines are important mediators of the immune system. They are involved in pathophysiological processes including autoimmunity and cancer development. In contrast to hormones, cytokines are produced by more than one cell type. Most cytokines act locally in an autocrine or paracrine fashion. Exceptions are cytokines, which enter the bloodstream and signal endocrine, or membrane-bound cytokines, which act juxtacrine. Cytokines are classified according to their function or structure, or based on the receptors they bind. The latter is a reasonable classification because cytokines bind to multimeric receptor complexes in which often one subunit is also found in receptor complexes utilized by other cytokines [1,2]. Accordingly, cytokines and cytokine receptors are subdivided into seven major families [3]. The largest family are class I cytokine receptors and corresponding cytokines. A central feature of class I cytokines is a common up-up-down-down topology of their four antiparallel α helices. Therefore, these cytokines have also been referred to as the α-helical bundle cytokine family [4]. Class I cytokines are further subdivided based on the shared receptor subunit [3]. One group are IL-6 family cytokines, which are defined as cytokines that use the common signaling receptor subunit gp130 and originally comprise eight cytokines—IL-6, IL-11, IL-27, oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1), and cardiotrophin-like cytokine factor 1 (CLCF1) [2]. IL-35, and IL-39 have been recently added to the family because they share gp130 in their receptor complexes [5]. A second group of class I cytokines are IL-12 family cytokines. Members of the IL-12 family form soluble heterodimers consisting of a four-helix-bundle α subunit (IL-23p19, IL-27p28 or IL-12p35) and a β subunit (Epstein–Barr virus-induced gene 3, EBI3 or IL-12p40), which is structurally related to soluble IL-6 receptor alpha (sIL-6Rα)[6]. At the moment, the IL-12 cytokine Cells 2020, 9, 2184; doi:10.3390/cells9102184 www.mdpi.com/journal/cells Cells 2020, 9, 2184 2 of 24 Cells 2020, 9, x 2 of 23 familyIL-6 receptor has five alpha members—IL-12, (sIL-6Rα) [6]. IL-23, At the IL-27, moment, IL-35 the and IL-12 IL-39 cytokine (Table 1family, Figure has1). five IL-27, members—IL-12, IL-35 and IL-39 areIL-23, shared IL-27, with IL-35 the IL-6and family.IL-39 (Table A possible 1, Figure sixth 1). member,IL-27, IL-35 called and IL-Y,IL-39 hasare currentlyshared with only the been IL-6 describedfamily. asA a geneticallypossible sixth engineered member, called heterodimer IL-Y, has IL-27p28 currently/IL-12p40 only been [7, 8described]. as a genetically engineered heterodimer IL-27p28/IL-12p40 [7,8]. Table 1. IL-12 Cytokine Family Members. Table 1. IL-12 Cytokine Family Members. α Subunits α Subunits p19p19 p28 p28 p35 p35 p40p40 IL-23IL-23 [9 [9]] IL-Y IL-Y [7,8] [7, 8]IL-12 [10–14] IL-12 [10 –14] β subunitsβ subunits EBI3EBI3 IL-39IL-39 [15 [15–17]–17] IL-27 IL-27 [18] [18 ]IL-35 [19,20] IL-35 [ 19,20] IL-12 IL-23 IL-27 IL-35 IL-39 p35 p19 p28 p35 p19 p40 p40 EBI3 EBI3 EBI3 IL-12Rβ1 IL-12Rβ1 WSX-1 WSX-1IL-12Rβ2 IL-12Rβ2 gp130 IL-23R IL-12Rβ2 IL-23R gp130 IL-12Rβ2 gp130 IL-12Rβ2 gp130 gp130 FigureFigure 1. 1.Cytokines Cytokines and and cognate cognate receptorsreceptors of the IL-12 family. family. Schematic Schematic overview overview of ofheterodimeric heterodimeric IL-12IL-12 type type cytokines cytokines and and their their cognate cognate receptors. receptors. IL-12, IL-12, composed composed of of IL-12p40 IL-12p40 and and IL-12p35, IL-12p35, binds binds to to the IL-12the receptorIL-12 receptor complex complex comprised comprised of two of receptors, two receptors, IL-12R βIL-12R1 andβ IL-12R1 and βIL-12R2. Theβ2. heterodimeric The heterodimeric cytokine IL-23cytokine is formed IL-23 by is IL-12p40formed by and IL-12p40 IL-23p19, and andIL-23p19, binds and the IL-23binds receptor the IL-23 complex receptor comprised complex comprised of IL-12R β1 andof IL-23R.IL-12Rβ1 EBI3 and andIL-23R. IL-27p28 EBI3 and form IL-27p28 IL-27, whichform IL-27, binds which to WSX-1 binds andto WSX-1 gp130, and the gp130, signal the transducer signal oftransducer IL-6. IL-35 of is IL-6. composed IL-35 is of composed EBI3 and of IL-12p35. EBI3 and FourIL-12p35. different Four IL-35different receptor IL-35 complexesreceptor complexes have been proposed:have been WSX-1 proposed:/IL-12R WSX-1/IL-12Rβ2, IL-12Rβ2β/gp130,2, IL-12R IL-12Rβ2/gp130,β2/IL-12R IL-12Rβ2β and2/IL-12R gp130β2/gp130. and gp130/gp130. The cytokine The IL-39, formedcytokine by IL-39, EBI3 andformed IL-23p19, by EBI3 binds and IL-23p19, to gp130 bi andnds IL-23R.to gp130 Ig-domains and IL-23R. areIg-domains shown as are circles shown and as in thecircles same and color in as the cytokine-binding same color as cytokine-binding homology region homology (CHR). Membrane region (CHR). proximal Membrane fibronectin-type-III proximal domainsfibronectin-type-III are presented domains in light are colors. presented The WSXWS in light colors. motifs The within WSXWS IL-12p40, motifs EBI3 within and IL-12p40, the receptors EBI3are indicatedand the byreceptors thick black are indicated lines and by conserved thick black cysteine lines and residues conserved by thin cysteine black lines.residues by thin black lines. Homodimeric members have also been described for IL-12p40 (p80) [21] and IL-27p28 (IL-30) [22]. Surprisingly,Homodimeric the IL-12 members family have is still also growing been described because for new IL-12p40 combinations (p80) [21] formingand IL-27p28 heterodimeric (IL-30) cytokines[22]. Surprisingly, containing the atIL-12 least family one is αstillor growingβ subunit because have new been combinations identified forming (IL-12p40 heterodimeric/CD5L [23 ], IL-12p35cytokines/CRLF1 containing [24], IL-6 at /leastEBI3 [one25], α IL-27p28 or β subunit/CRLF1 have [22], been IL-27p28 identifi/sIL-6Red (IL-12p40/CD5L [26]). Receptor [23], complexes IL- 12p35/CRLF1 [24], IL-6/EBI3 [25], IL-27p28/CRLF1 [22], IL-27p28/sIL-6R [26]). Receptor complexes of of IL-12 family cytokines are also heterodimeric and consist of IL-12Rβ1, IL-12Rβ2, IL-23R, WSX-1 IL-12 family cytokines are also heterodimeric and consist of IL-12Rβ1, IL-12Rβ2, IL-23R, WSX-1 and and gp130 (Figure1,[ 27]). IL-12 signals via IL-12Rβ1 and IL-12Rβ2, and IL-23 signals via IL-12Rβ1 gp130 (Figure 1, [27]). IL-12 signals via IL-12Rβ1 and IL-12Rβ2, and IL-23 signals via IL-12Rβ1 and and IL-23R, whereas IL-27 and IL-35 shares receptor subunits with the IL-6 family (gp130/WSX1 and IL-23R, whereas IL-27 and IL-35 shares receptor subunits with the IL-6 family (gp130/WSX1 and gp130/IL-12Rβ2, gp130/gp130, IL-12Rβ2/IL-12Rβ2, WSX1/IL-12Rβ2, respectively) [6]. Using engineered gp130/IL-12Rβ2, gp130/gp130, IL-12Rβ2/IL-12Rβ2, WSX1/IL-12Rβ2, respectively) [6]. Using chimericengineered cytokine chimeric receptors cytokine we receptors showed, we that showed additional, that combinations additional combinations of receptors of are receptors possible are [28 ]. Basedpossible on their[28]. sharedBased on use their of gp130 shared IL-6 use and of gp13 IL-120 cytokinesIL-6 and IL-12 are oftencytokines considered are often members considered of the IL-6members/IL-12 familyof the IL-6/IL-12 comprising family both comprising IL-6 and both IL-12 IL family-6 and IL-12 cytokines family [ cytokines29]. Functionally, [29]. Functionally, IL-6/IL-12 cytokinesIL-6/IL-12 are cytokines key regulators are key of regulators the immune of the system. immune They system. have They pleiotropic have pleiotropic functions andfunctions play criticaland rolesplay in critical multiple roles immune in multiple responses, immune and responses, a variety ofand physiological a variety of andphysiological pathological and processes pathological [27].
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