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CHaPTEr 9 Cytokines and Cytokine Receptors 131

Type I/II cytokine TNF receptor IL-1 Receptor tyrosine TGF-β
receptors family family receptor family kinases family receptor family

FIG 9.1 Schematic representation of prototypical receptors from five of the major cytokine
receptor superfamilies.

Cytokines cytoplasmic portion of these receptors, two segments of homology
IL-12 Th1 IFN-y can be discerned, termed Box 1 and Box 2 motifs. The membrane
STAT4 T-bet proximal domain binds Janus kinases (JAKs; see below). Some
of the cytokine receptors are homodimers, such as the receptors
for EPO, TPO, PRL, and possibly leptin, whereas other receptors
IL-4 for type I cytokines are heterodimers, containing two distinct
IL-4 Th2 IL-5
STAT6 Gata3 receptor subunits. On the basis of this characteristic, the type I
IL-13
family of receptors can be divided into subfamilies. Each member
of the subfamily uses a shared receptor subunit in conjunction
IL-4, IL-21 IL-9 with a ligand-specific subunit. For example, the receptors for
TGFβ-1 Th9 PU.1 IL-10 IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 all use a common cytokine
STAT6 IRF4
γ chain, γc (see Table 9.1), whereas a common β chain, βc, is
shared by IL-3, IL-5, and GM-CSF. Similarly, gp130 is a shared
IL-6, IL-21 IL-17A subunit for IL-6 family cytokines (IL-6, IL-11, IL-27, IL-35, CNTF,
IL-23, TGFβ-1 Th17 Rorγt LIF, OSM, and CT-1). IL-12 and IL-23 also share a receptor
STAT3, IL-1 IL-17F
Naive CD4 + subunit, as do members of the IL-10 family.
T ceII Other levels of shared receptor usage also exist. For example,
IL-6 IL-13 the receptors for LIF, CNTF, OSM, and CT-1 all share the LIF
TNF-α Th22 Rorγt IL-22 receptor subunit, IL-31 and OSM also share one receptor chain,
STAT3 AHR IL-21
whereas IL-2 and IL-15 utilize the same β and γ c chains. Con-
versely, IL-4 can bind two different receptor complexes. The
IL-6 classic IL-4 receptor is composed of the IL-4Rα chain and the
IL-21 Tfh Bci-6 IL-21
STAT3 γc chain. Additionally, IL-4 can also bind the IL-13 receptor,
which comprises a heterodimer of the IL-4Rα chain and the
IL-13Rα chain. IL-13 only utilizes the IL-13 receptor complex
IL-10 for signaling.
IL-2
STAT5 iTreg Foxp3 IL-35 The utilization of common receptor subunits explains the
TGFβ-1
phenomenon of shared biological activities (cytokine redundancy)
FIG 9.2 Differentiation of T-helper cell subtypes. between cytokines that belong to the same subfamily. Within a
subfamily, actions distinct for each cytokine can be attributed,
at least in part, to the ligand-specific subunits. The pleiotropic
effects of a single cytokine can be accounted for by the existence
IL-19, IL-20, IL-22, IL-24, IL-26, and the IFN-related cytokines of more than one receptor for that cytokine.
IL-28A (IFN-λ2), IL-28B (IFN-λ3), IL-29 (IFN-λ1), which bind
type II receptors. The ligands and receptors in this superfamily Family Members and Their Actions
are structurally similar and utilize related molecules for signal Homodimeric Receptors
transduction. 5,6 Many of the cytokines that use homodimeric receptors are classic
A central feature of type I cytokines is a similarity in their hormones. These include EPO GH, PRL, and leptin. EPO is
basic structure. Each contains four antiparallel α helices with required for erythrocyte growth and development and is widely
two long and one short loop connections arranged in an up–up/ used to treat anemia. Similarly, TPO is required for megakaryocyte
down–down configuration. Because of this structure, these development and may have a use in the treatment of thrombo-
cytokines have also been referred to as the α-helical bundle cytokine cytopenia. G-CSF not only regulates the production of neutrophils
family. through its action on committed progenitor cells but also supports
Structurally, the receptors in the type I family have conserved the survival of mature neutrophils, enhancing their functional
cysteine residues, a conserved Trp–Ser–X–Trp–Ser motif (where capacity. G-CSF is widely used clinically to treat patients with
X indicates any amino acid), and fibronectin-like repeats in their granulocytopenia. As one would predict, G-CSF–deficient mice
extracellular domains. These receptors have a single transmem- have marked neutropenia, and mutations of the G-CSF receptor
brane domain and divergent cytoplasmic domains. Within the (G-CSFR) result in severe congenital neutropenia in humans.