The most widely used classification of cytokines is based on homologous secondary structural features and classification of cytokine receptors is based on structural homologies of the extracellular cytokine-binding domains and shared intracellular signaling mechanisms (Fig. 1). Signaling mechanisms utilized by individual families are considered in the section that follows. The TGF-β family is one widely studied family of growth factors not included in the classification in Fig. 1, and its signaling mechanism is discussed later.
Fig1. Structure of cytokine receptors. (A) Receptors for different cytokines are classified into families on the basis of conserved extracellular domain structures and signaling mechanisms. Representative cytokines or other ligands that bind to each receptor family are listed below the schematic drawings. (B) Groups of cytokine receptors share identical or highly homologous subunit chains. Selected examples of cytokine receptors in each group are shown. In the common γ chain family, the interleukin-2 (IL-2) and IL-15 receptors (IL-15R) share a β chain, CD122. In the common β chain family, the shared β chain is CD131. CD40L, CD40 ligand; FASL, FAS ligand; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN, interferon; IRAK, IL-1 receptor–associated kinase; LT, lymphotoxin; TRAF, TNF receptor–associated factor; TNF, tumor necrosis factor; TRADD, TNF receptor–associated death domain; WSXWS, tryptophan-serine-X-tryptophan-serine.
Type I Cytokines and Receptors (Hematopoietin Receptor Family)
Type I cytokines have four α-helical bundles and the conserved sequences of the type I cytokine receptors form homologous structures that bind these bundles. Type I cytokine receptors are dimers or trimers that typically consist of unique ligand binding chains and one or more signal-transducing chains, the latter often shared by receptors for different cytokines. These chains contain one or two domains with a conserved pair of cysteine residues and a membrane proximal peptide stretch containing a tryptophan-serine-X-tryptophan-serine (WSXWS) motif, where X is any amino acid (see Fig. 1A). The specificity for individual cytokines is determined by amino acid residues in the ligand-binding domains that vary from one receptor to another. This receptor family can be divided into subgroups based on structural homologies or the use of shared signaling polypeptides (see Fig. 1B). One group, which includes receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, contains a signaling component called the common γ chain (γc, or CD132). Within this subgroup, some receptors share one of two β chain subunits (CD122 or CD131), and some lack a β chain. Another subgroup of type I cytokine receptors, including those for IL-6, IL-11, IL-27, LIF, CNTR, and Ocostatin-M among others, uses the gp130 signaling chain. All the type I cytokine receptors engage JAK-STAT signaling pathways.
Type II Cytokine Receptors (Interferon Receptor Family)
Cytokines that bind type II cytokine receptors include interferons, IL-10, IL-20, and IL-22. The type II receptors are simi lar to type I receptors by virtue of possessing two extracellular domains with conserved cysteines, but type II receptors do not contain the WSXWS motif. All of the type II cytokine receptors, like the type I receptors, engage JAK-STAT signaling pathways.
TNF and TNF Receptor Families
The TNF family includes both secreted soluble cytokines, such as TNF and lymphotoxin, and membrane-bound ligands, such as FASL and CD40L. Both the secreted cytokines and the mem brane-bound TNF-family ligands form homotrimers, and they bind to preformed trimeric receptors, which are members of a large TNF receptor (TNFR) family (also called the TNFR super family). TNFR proteins share conserved cysteine-rich extracellular domains and intracellular signaling mechanisms that typically stimulate gene expression, but in some cases induce apoptosis. Some of the best studied receptors of this family will be discussed below, while others will be described in other chapters in their biologic contexts; these receptors include the TNF receptors, TNFRI and TNFRII; the CD40 protein, FAS; the lymphotoxin receptor; and the BAFF receptor family, among others.
Binding of the ligands to the preformed trimeric receptors typically induces a conformational change and recruits adaptor proteins to the receptor complex. These adaptors in turn recruit enzymes that include both E3 ubiquitin ligases, which mediate nondegradatory polyubiquitination, and protein kinases, which initiate downstream signaling. In the case of the TNF receptor illustrated in Fig. 2 the receptor recruits the adaptor protein TNF receptor–associated death domain (TRADD), and TRADD in turn can recruit proteins called TNF receptor associated factors (TRAFs), which possess a unique type of E3 ligase activity that will be discussed in the section on NF-κB signaling. The type I TNF receptor (there are two different receptors for TNF) and Fas (CD95) can also recruit adaptors that lead to the activation of caspase-8, and these receptors can thereby induce apoptosis in certain cells (discussed later).
Fig2. Signaling through the tumor necrosis factor (TNF) receptor can result in nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinase activation or in the induction of apoptotic death. Ligation of the type I TNF receptor results in the recruitment of an adaptor protein called TNF receptor–associated death domain (TRADD), which in turn can activate TNF receptor–associated factor (TRAF) molecules (E3 ubiquitin ligases) and the RIP1 kinase. Downstream consequences include the activation of the NF-κB path way and the c-Jun N-terminal kinase (JNK) MAP kinase pathway or the induction of apoptotic death.
Interleukin-1 Family
IL-1 family members include IL-1α, IL-1β, IL-18, IL-33 and IL-36. The receptors of this family share a conserved cytosolic sequence, called the Toll/IL-1 receptor (TIR)domain, and engage similar signal transduction pathways that induce new gene transcription. We discussed TLR signaling in Chapter 4. Briefly, engagement of the IL-1R or of TLRs results in receptor dimerization and the recruitment of one or more of four known TIR domain–containing adaptors to the TIR domain of the cytoplasmic tail of the receptor. The adaptors link TLRs to different members of the IL-1 receptor–associated kinase (IRAK) family. IRAKs can in turn link adaptors to TRAF6, an E3 ubiquitin ligase required for NF-κB activation. Other events downstream of TLR signaling include MAP kinase activation and the phosphorylation of IRF3 and IRF7, inducers of type I interferon transcription. The latter aspect of TLR signaling has been considered in the context of the antiviral state in Chapter 4. Different adaptors link TLRs to NF-κB signaling, MAP kinase activation, and the activation of IRF3. The mechanisms connecting IL-1R/TLR signaling and NF-κB activation are dis cussed later. One unique aspect of the regulation of IL-1R family signaling is the existence of a number of secreted inhibitory cytokines that block inflammatory effects of the proinflammatory IL-1 family cytokines. These include IL-1RA and IL-36RA, which are competitive antagonists of IL-1 and IL-36 binding to their receptors, respectively.
Interleukin-17 Family
There are many different cytokines of the IL-17 family and, in subsequent chapters, the emphasis will largely be on the cytokines that are best characterized in the context of autoimmunity and inflammation, namely IL-17A and IL-17F. IL-17 B, C, and D remain poorly characterized, and IL-17E, also known as IL-25, drives Th2 responses. The receptors of this family are preformed oligomers that include various combinations of the IL-17R A, B, C, D, and E chains. IL-17A homodimers and IL-17F homodimers engage preformed heterodimers made up of IL-17RA and IL-17RC. IL-17E/IL-25 engages a dimer containing IL-17RB and IL-17RA. Receptor oligomers include at least one molecule of the IL-17RA chain. Each receptor chain is a type I integral membrane protein that contains two extracellular type III Fibronectin domains and an intracellular SEFIR motif, which has partial homology to the TIR motif discussed in the context of IL-1 receptor signaling. In the context of IL-17R signaling, this motif binds to an adaptor ACT1 that also contains a SEFIR motif and contributes to the recruitment of TRAF6 and leads to NF-κB activation. Additional cytoplasmic motifs are required for the activation of many other pathways, including the ERK pathway and the C/EBP family of transcription factors.
