The hematopoietin receptor family (also known as the class I cytokine receptor family) is the largest of the cytokine receptor families and comprises a number of structurally related type I membrane-bound glycoproteins. The cytoplasmic domains of these receptors associate with nonreceptor tyrosine kinase molecules, including the Jak kinases and src family kinases. After ligand binding and receptor oligomerization, these associated nonreceptor tyrosine kinases phosphorylate intracellular substrates, which leads to signal transduction. Most of the multiple-chain receptors in the hematopoietin receptor family consist of a cytokine-specific α chain subunit paired with one or more shared receptor subunits. Five shared receptor subunits have been described to date: (1) the common γ chain (γc), (2) the common β chain shared between the IL-2 and IL-15 receptors; (3) a distinct common β chain shared between the granulocyte-macrophage colony stimulating factor (GM-CSF), IL-3, and IL-5 receptors; (4) the IL-12Rβ2 chain shared by the IL-12 and IL-23 receptors; and (5) finally the glycoprotein 130 (gp130) molecule, which participates in signaling by IL-6 and related cytokines.
Cytokines with Receptors that Include the γC Chain
The receptor complexes using the γc chain are the IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, and IL-21 receptors. Two of these receptors, IL-2R and IL-15R, also use the IL-2Rβc chain. The γc chain is physically associated with Jak3, and activation of Jak3 is critical to most signaling initiated through this subset of cytokine receptors.20
Interleukin 2 and Interleukin 15
IL-2 and IL-15 can each activate NK cells and stimulate proliferation of activated T cells. IL-2 is a product of activated T cells, and IL-2R is largely restricted to lymphoid cells. The IL-15 gene is expressed by nonlymphoid tissues, and its transcription is induced by UVB radiation in keratinocytes and fibroblasts and by LPS in monocytes and dendritic cells. Multiple isoforms of IL-15Rα are found in various hematopoietic and nonhematopoietic cells. The IL-2R and IL-15R complexes of lymphocytes incorporate up to three receptor chains, whereas most other cytokine receptor complexes have two. The affinities of IL-2R and IL-15R for their respective ligands can be regulated, and to some extent, IL-2 and IL-15 compete with each other. The highest affinity receptor complexes for each ligand (approximately 10−11 M) consist of the IL-2Rβc and γc chains, as well as their respective α chains (IL-2Rα, also known as CD25, and IL-15Rα). γc and IL-2Rβc without the α chains form a functional lower affinity receptor for either ligand (10−8 to 10−10 M). Although both ligands transmit signals through the γc chain, those signals elicit overlapping but distinct responses in various cells. Activation of naive CD4 T cells by T-cell receptor and costimulatory molecules induces expression of IL-2, IL-2Rα, and IL-2Rβc, which leads to vigorous proliferation. Prolonged stimulation of T-cell receptor and IL-2R leads to expression of FasL and activation-induced cell death. Although IL-2 signaling facilitates the death of CD4 T cells in response to sustained exposure to antigen, IL-15 inhibits IL-2-mediated activation-induced cell death as it stimulates growth. Similarly, IL-15 promotes proliferation of memory CD8 T cells, whereas IL-2 inhibits it. IL-15 is also involved in the homeostatic survival of memory CD8 T cells, NK cells, and NK T cells. These contrasting biologic roles are illustrated by mice deficient in IL-2 or IL-2Rα that develop autoimmune disorders, and mice deficient in IL-15 or IL-15Rα, which have lymphopenia and immune deficiencies. Thus, IL-15 appears to have an important role in promoting effector functions of antigen-specific T cells, whereas IL-2 is involved in reining in autoreactive T cells.21
Interleukin 4 and Interleukin 13
IL-4 and IL-13 are products of activated Th2 cells that share limited structural homology (approximately 30%) and overlapping but distinct biologic activities. A specific receptor for IL-4, which does not bind IL-13, is found on T cells and NK cells. It consists of IL-4Rα (CD124) and γc and transmits signals via Jak1 and Jak3. A second receptor complex that can bind either IL-4 or IL-13 is found on keratinocytes, endothelial cells, and other nonhematopoietic cells. It consists of IL-13Rα1 and IL-4Rα and transmits signals via Jak1 and Jak2. These receptors are expressed at low levels in resting cells, and their expression is increased by various activating signals. Curiously, exposure of monocytes to IL-4 or IL-13 suppresses expression of IL-4Rα and IL-13Rα1, whereas the opposite effect is observed in keratinocytes. Both signal transduction pathways appear to converge with the activation of STAT6, which is both necessary and sufficient to drive Th2 differentiation. IL-13Rα2 is a cell surface receptor homologous to IL-13Rα1 that specifically binds to IL-13 but is not known to transmit any signals.20
The biologic effects of engagement of the IL-4 receptor vary depending on the specific cell type, but most pertain to its principal role as a growth and differentiation factor for Th2 cells. Exposure of naive T cells to IL-4 stimulates them to proliferate and differentiate into Th2 cells, which produce more IL-4, which in turn leads to autocrine stimulation that prolongs Th2 responses. Thus the expression of IL-4 early in the immune response can initiate a cascade of Th2 cell development that results in a predominately Th2 response. The genes encoding IL-4 and IL-13 are located in a cluster with IL-5 that undergoes structural changes during Th2 differentiation that are associated with increased expression. Although naive T cells can make low levels of IL-4 when activated, IL-4 is also produced by activated NK T cells. Mast cells and basophils also release preformed IL-4 from secretory granules in response to FcϵRI-mediated signals. A prominent activity of IL-4 is the stimulation of class switching of the immunoglobulin genes of B cells. Nuocytes and natural helper cells are recently identified populations of innate immune effector cells that provide an early source of IL-13 during helminth infection. As critical factors in Th2 differentiation and effector function, IL-4 and IL-13 are mediators of atopic immunity. In addition to controlling the behavior of effector cells they also act directly on resident tissue cells, such as in inflammatory airway reactions.22
Interleukin 9 and Interleukin 21
IL-9 is a product of activated Th2 cells exposed to TGF-β that acts as an autocrine growth factor as well as a mediator of inflammation.23 It is also produced by mast cells in response to IL-10 or stem cell factor. It stimulates proliferation of T and B cells and promotes expression of immunoglobulin E by B cells. It also exerts proinflammatory effects on mast cells and eosinophils. IL-9-deficient mice exhibit deficits in mast cell and goblet cell differentiation. IL-9 can be grouped with IL-4 and IL-13 as cytokines that function as effectors of allergic inflammatory processes and may play an important role in asthma and allergic disorders. IL-21 is also a product made by the Th2, Th17, and Tfh lineages that signals through a receptor composed of a specific α chain (IL-21R) homologous to the IL-4R α chain and γc.24 Absence of an intact IL-21 receptor is associated with impaired Th2 responses.25
Interleukin 7 and Thymic Stromal Lymphopoietin
Mutations abrogating the function of IL-7, IL-7Rα (CD127), γc, or Jak3 in mice or humans cause profound immunodeficiency as a result of T- and NK-cell depletion.20 This is principally due to the indispensable role of IL-7 in promoting the expansion of lymphocytes and regulating the rearrangement of their antigen receptor genes. IL-7 is a potent mitogen and survival factor for immature lymphocytes in the bone marrow and thymus. The second function of IL-7 is as a modifier of effector cell functions in the reactive phase of certain immune responses. IL-7 transmits activating signals to mature T cells and certain activated B cells. Like IL-2, IL-7 has been shown to stimulate proliferation of cytolytic T cells and lymphokine-activated killer cells in vitro and to enhance their activities in vivo. IL-7 is a particularly significant cytokine for lymphocytes in the skin and other epithelial tissues. It is expressed by keratinocytes in a regulated fashion, and this expression is thought to be part of a reciprocal signaling dialog between dendritic epidermal T cells and keratinocytes in murine skin. Keratinocytes release IL-7 in response to IFN-γ, and dendritic epidermal T cells secrete IFN-γ in response to IL-7.
An IL-7-related cytokine using one chain of the IL-7 receptor as part of its receptor is thymic stromal lymphopoietin (TSLP). TSLP was originally identified as a novel cytokine produced by a thymic stromal cell line that could act as a growth factor for B- and T-lineage cells. The TSLP receptor consists of the IL-7Rα and a second receptor chain (TSLPR) homologous to but distinct from the γc chain. TSLP has attracted interest because of its ability to prime dendritic cells to become stronger stimulators of Th2 cells. This activity may permit TSLP to foster the development of some types of allergic diseases.26,27
Cytokines with Receptors Using the Interleukin 3 Receptor β Chain
The receptors for IL-3, IL-5, and GM-CSF consist of unique cytokine-specific α chains paired with a common β chain known as IL-3Rβ or βc (CD131). Each of these factors acts on subsets of early hematopoietic cells.28 IL-3, which was previously known as multilineage colony-stimulating factor, is principally a product of CD4+ T cells and causes proliferation, differentiation, and colony formation of various myeloid cells from bone marrow. IL-5 is a product of Th2 CD4+ cells and activated mast cells that conveys signals to B cells and eosinophils. IL-5 has a costimulatory effect on B cells in that it enhances their proliferation and immunoglobulin expression when they encounter their cognate antigen. In conjunction with an eosinophil-attracting chemokine known as CC chemokine ligand 11 or eotaxin, IL-5 plays a central role in the accumulation of eosinophils that accompanies parasitic infections and some cutaneous inflammatory processes. IL-5 appears to be required to generate a pool of eosinophil precursors in bone marrow that can be rapidly mobilized to the blood, whereas eotaxin's role is focused on recruitment of these eosinophils from blood into specific tissue sites. GM-CSF is a growth factor for myeloid progenitors produced by activated T cells, phagocytes, keratinocytes, fibroblasts, and vascular endothelial cells. In addition to its role in early hematopoiesis, GM-CSF has potent effects on macrophages and dendritic cells. In vitro culture of fresh Langerhans cells in the presence of GM-CSF promotes their transformation into mature dendritic cells with maximal immunostimulatory potential for naive T cells. The effects of GM-CSF on dendritic cells probably account for the dramatic ability of GM-CSF to evoke therapeutic antitumor immunity when tumor cells are engineered to express it.29,30
Interleukin 6 and Other Cytokines with Receptors Using Glycoprotein 130
Receptors for a group of cytokines including IL-6, IL-11, IL-27, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1 interact with a hematopoietin receptor family member, gp130, which does not appear to interact with any ligand by itself. The gp130 molecule is recruited into signaling complexes with other receptor chains when they engage their cognate ligands.
IL-6 is the most thoroughly characterized of the cytokines that use gp130 for signaling and serves as a paradigm for discussion of the biologic effects of this family of cytokines. IL-6 is yet another example of a highly pleiotropic cytokine with multiple effects. A series of different names (including IFN-β2, B-cell stimulatory factor 2, plasmacytoma growth factor, cytotoxic T cell differentiation factor, and hepatocyte-stimulating factor) were used for IL-6 before it was recognized that a single molecular species accounts for all of these activities. IL-6 acts on a wide variety of cells of hematopoietic origin. IL-6 stimulates immunoglobulin secretion by B cells and has mitogenic effects on B lineage cells and plasmacytomas. IL-6 also promotes maturation of megakaryocytes and differentiation of myeloid cells. Not only does it participate in hematopoietic development and reactive immune responses, but IL-6 is also a central mediator of the systemic acute-phase response. Increases in circulating IL-6 levels stimulate hepatocytes to synthesize and release acute-phase proteins.
There are two distinct signal transduction pathways triggered by IL-6. The first of these is mediated by the gp130 molecule when it dimerizes on engagement by the complex of IL-6 and IL-6Rα. Homodimerization of gp130 and its associated Jak kinases (Jak1, Jak2, Tyk2) leads to activation of STAT3. A second pathway of gp130 signal transduction involves Ras and the mitogen-activated protein kinase cascade and results in phosphorylation and activation of a transcription factor originally designated nuclear factor of IL-6.
IL-6 is an important cytokine for skin and is subject to dysregulation in several human diseases, including some with skin manifestations. IL-6 is produced in a regulated fashion by keratinocytes, fibroblasts, and vascular endothelial cells as well as by leukocytes infiltrating the skin. IL-6 can stimulate the proliferation of human keratinocytes under some conditions. Psoriasis is one of several inflammatory skin diseases in which elevated expression of IL-6 has been described. Human herpesvirus 8 produces a viral homolog of IL-6 that may be involved in the pathogenesis of human herpes virus-8-associated diseases, including Kaposi sarcoma and body cavity-based lymphomas.
The other cytokines using gp130 as a signal transducer have diverse bioactivities. IL-11 inhibits production of inflammatory cytokines and has shown some therapeutic activity in patients with psoriasis. Exogenous IL-11 also stimulates platelet production and has been used to treat thrombocytopenia occurring after chemotherapy. IL-27 is discussed in the next section with the IL-12 family of cytokines.
Interleukin 12, Interleukin 23, Interleukin 27, and Interleukin 35: Pivotal Cytokines Regulating T Helper 1 and T Helper 17 Responses
IL-12 is different from most other cytokines in that its active form is a heterodimer of two proteins, p35 and p40. IL-12 is principally a product of antigen-presenting cells such as dendritic cells, monocytes, macrophages, and certain B cells in response to bacterial components, GM-CSF, and IFN-γ. Activated keratinocytes are an additional source of IL-12 in skin. Human keratinocytes constitutively make the p35 subunit, whereas expression of the p40 subunit can be induced by stimuli including contact allergens, phorbol esters, and UV radiation.
IL-12 is a critical immunoregulatory cytokine that is central to the initiation and maintenance of Th1 responses. Th1 responses that are dependent on IL-12 provide protective immunity to intracellular bacterial pathogens. IL-12 also has stimulatory effects on NK cells, promoting their proliferation, cytotoxic function, and the production of cytokines, including IFN-γ. IL-12 has been shown to be active in stimulating protective antitumor immunity in a number of animal models.31
Two chains that are part of the cell surface receptor for IL-12 have been cloned. Both are homologous to other β chains in the hematopoietin receptor family and are designated β1 and β2. The β1 chain is associated with Tyk2 and the β2 chain interacts directly with Jak2. The signaling component of the IL-12R is the β2 chain. The β2 chain is expressed in Th1 but not Th2 cells and appears to be critical for commitment of T cells to production of type 1 cytokines. IL-12 signaling induces the phosphorylation of STAT1, STAT3, and STAT4, but it is STAT4 that is essential for induction of a Th1 response.
IL-23 is a heterodimeric cytokine in the IL-12 family that consists of the p40 chain of IL-12 in association with a distinct p19 chain. IL-23 has overlapping activities with IL-12, but also induces proliferation of memory T cells. Interest in IL-23 has been sparked by the observation that IL-23 promotes the differentiation of T cells producing IL-17 (Th17 subset). The IL-23 receptor consists of two chains: (1) the IL-12Rβ1 chain that forms part of the IL-12 receptor and (2) a specific IL-23 receptor.32
The third member of the IL-12 family to be discovered was IL-27. IL-27 is also a heterodimer and consists of a subunit called p28 that is homologous to IL-12 p35 and a second subunit known as EBI3 that is homologous to IL-12 p40. IL-27 plays a role in the early induction of the Th1 response. The IL-27 receptor consists of a receptor called WSX-1 that associates with the shared signal-transducing molecule gp130.32,33
The newest member of the IL-12 family is IL-35. The IL-35 heterodimer is composed of the p35 chain of IL-12 associated with the IL-27β chain EBI3. In contrast to the other IL-12 family cytokines, IL-35 is selectively made by Treg cells, promotes the growth of Treg cells, and suppresses the activity of Th17 cells.34
The IL-12 family of cytokines has emerged as a promising new target for anticytokine pharmacotherapy. The approach that has been developed the furthest to date is targeting both IL-12 and IL-23 with monoclonal antibodies directed against the p40 subunit that is part of both cytokines. Ustekinumab is an antihuman p40 monoclonal antibody that has shown therapeutic activity against psoriasis comparable to that of TNF inhibitors and has received FDA approval for the treatment of psoriasis.35 The development of anti-p40 therapies is several years behind anti-TNF-α drugs, but development of additional anti-p40 biologics for clinical use is anticipated.