Mediators of Inflammation: Cytokines and Adhesion Molecules

Cytokine Family

The cytokine family of proteins is remarkably extensive: more than 100 known members have been identified. Consequently, there are a number of overlapping nomenclature and classification systems for cytokines based on biological function, receptor binding properties, originating cell type, and common structural motifs ( ). Cytokine families based on cell family and function include the TNF, IL, and IFN families; CSFs, growth factors, and adipokines ( Table 49.1 ). Each member of the TNF family is the product of a separate gene. However, there are considerable overlaps in biological properties of TNF proteins ( ). The TNF/TNF receptor superfamily mediates cellular differentiation, survival, and death and coordinates organ development ( ). Within the IL family, subfamilies are the IL-1 family, with members including IL-1α, IL-1β, IL-18, IL-33, IL-36, IL-37, and IL-38; the common γ chain cytokine family including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21; the IL-6 family, including IL-6, leukemia inhibitory factor, IL-11, oncostatin, ciliary neurotropic factor, and cardiotropin I; and the IL-10 family, including IL-10, IL-19, IL-20, IL-22, IL-23, IL-26, IL-28A and IL-28B and IL-29 (IFN-λ); the IL-12 family (IL-12, IL-23, IL-27 and IL-35); cytokines of the type 2 immune response (IL-5, IL-13, IL-25, IL-31 and TSLP) and the IL-17 family ( ). The CSFs are IL-3, granulocyte-CSF (G-CSF), granulocyte-macrophage-CSF (GM-CSF), and macrophage-CSF. Similar to the TNF family, CSFs have overlapping functions, in the case of CSFs, initiation of cell division in responding cells, but are distinct gene products with specific receptors ( ). Other cytokines, including IL-1β, IL-2, IL-4, IL-6, IL-7, IL-15, fibroblast growth factors (FGFs), transforming growth factors-β (TGFs-β), TGF-α, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), erythropoietin, insulin-like growth factor-1 (IGF-1), IGF-2, TNF-α, IFN-γ, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF), also function as growth factors ( ). IFN cytokines such as IFN-α and IFN-β promote innate and adaptive immune responses ( ). Angiogenic cytokines include vascular endothelial growth factor (VEGF), IL-1, IL-6, and IL-8. Adipokines mediate communication between adipose tissue and other key metabolic organs (liver, muscle, pancreas, and central nervous system) ( ). The adipokine family includes all products of cells localized in white adipose tissue. The best characterized of these are leptin (regulates body weight, proinflammatory), adiponectin (anti-inflammatory), resistin (insulin resistance), and secreted frizzled-related protein 5 (Sfrp5; anti-inflammatory, plays role in adipogenesis), as well as vaspin, visfatin, apelin, serum amyloid A, angiotensinogen, omentin, chemerin, zinc-α ₂ -glycoprotein (ZAG), IL-6, and TNF-α ( ; ). The osteoclast-activating cytokine receptor activator of nuclear factor-κB ligand (RANKL) is a member of the TNF superfamily. RANKL binds to its receptor RANK expressed on the membranes of osteoclast progenitors and induces osteoclast differentiation and activation. Binding of RANKL to the decoy receptor osteoprotegerin (OPG) interrupts osteoclastogenesis and prevents excessive bone resorption ( ). The extensive chemokine family is described separately later in this chapter.

Cytokine Receptors

Clinically, it may be useful to also group cytokines according to the structural homology of their receptors, as some drugs target cytokine-receptor interactions. Receptor homology partially accounts for the cytokine functional pleiotropy and redundancy described earlier. Cytokine signaling is initiated when cytokines bind the extracellular domains of their transmembrane protein receptors, which leads to activation of cytosolic proteins that are responsible for regulating gene transcription in the nucleus and thereby controlling cell proliferation, differentiation, maturation, and survival ( ).

There are five major cytokine receptor types ( Table 49.2 ): (1) IL-1 receptors characterized by three immunoglobulin (Ig)-like domains; (2) TNF receptors (TNFRs), whose members share a conserved cysteine-rich common extracellular binding domain; (3) class I cytokine receptors (or hematopoietin receptors), which lack intrinsic tyrosine kinase activity; (4) class II cytokine receptors, which also lack intrinsic tyrosine kinase activity; and (5) chemokine receptors (discussed separately later in this chapter).

Class I and class II receptors share a conserved extracellular region, the cytokine receptor homology domain (CHD), but are classified based on the CHD divergence. Class I receptors have two pairs of cysteines linked through a disulfide bond and a C-terminal WSXWS motif, whereas class II receptors also have two pairs of cysteines but lack the WSXWS motif ( ).

Lacking tyrosine kinase activity, the class I and class II receptors communicate with the Janus kinase (JAK) family of tyrosine kinases and one member of the TYK kinase family. Cytokine-receptor interaction results in the phosphorylation and activation of the appropriate JAK/TYK kinases and phosphorylation of the intracellular domains of the receptors. Phosphorylated tyrosine residues in the receptors bind members of the STAT (signal transducers and activation of transcription) family of cytoplasmic transcription proteins, leading to phosphorylation and dissociation from their receptor complexes. Once dissociated, the STAT proteins dimerize and translocate into the cell nucleus, where they bind DNA recognition sequences and function as transcription factors.

Class I receptors also make use of the RAS-RAF-MAP kinase and PI3 pathways to initiate gene transcription. Subfamilies of the class I receptors include the G-protein gp130, common gamma chain (γ _c , or CD132), and common beta chain (β _c , or CD131) receptors ( ). Cytokines such as IL-6 and IL-11, which share the G-protein–coupled seven-transmembrane receptors, signal via the gp130 signal-transducing molecule. Cytokines that utilize the γ _c receptors signal via JAK3 kinase. The β _c receptors recognize IL-3, IL-5, and GM-CSF and initiate signaling via JAK2 kinase ( ). Class II cytokine receptors recognize the IFN cytokines, IL-10, and others. Proinflammatory IFNs signal predominantly through STAT1, whereas the anti-inflammatory cytokine IL-10 signals primarily through STAT3. Therefore, STAT1 and STAT3 play opposing roles in cell survival and proliferation ( ). The IL-1 receptor family consists of four receptor complexes, two decoy receptors, and two negative regulators. Signaling occurs via the MyD88 adaptor ( ). The TNFR family consists of 29 members including TNFR1, TNFR2, OPG, and RANK ( ) and are key regulators of the immune response. Some members of the TNFR family, such as TNFR1, contain a death domain, and ligand binding initiates processes leading to cell death ( ).

The IL17 receptor family consists of five subunits, including IL-17RA-D with IL-17RA serving as a co-receptor, which is used by several of the six IL-17 family ligands (IL-17A-F) ( ). The IL17R family all have a conserved cytoplasmic domain, which is known as the SEFIR domain and related to the Toll/IL-R′ (TIR) domain. Connection to IκB kinase and stress-activated protein kinases (CIKS), also known as Act1, is a cytosolic adaptor protein, which is required for the activation of IL-17 signaling ( ; ). The cytoplasmic tail of IL17RA also has a distal domain that negatively regulates signaling, whereas the extracellular regions contain two fibronectin III–like domains, which mediate ligand binding and protein–protein interactions ( ; ). IL-17 has been shown to activate NF-κb signaling, leading to secretion of proinflammatory cytokines ( ; ). Furthermore, IL-17 can regulate tissue-specific genes with diverse physiologic functions, such as occluding in gut epithelia, mucin 1, kallikrein 1, RANKL, and osteoprotegerin ( ; ).

In addition, endocytosis is a key mechanism involved in cytokine receptor signaling. Recent reports have demonstrated that PI3K can control cytokine receptor endocytosis through both kinase activity-dependent and -independent mechanisms ( ).

In summary, cytokines are produced, released, and recognized by many different cell types. The extent of influence of these soluble proteins can be long range (systemic) when released into the circulation or their action may be highly localized, producing effects only on the cell releasing them or on its neighboring cells, and downstream signaling is dependent on the cytokine receptor class and structure as well as cell and tissue type.

Cytokines In Disease States

Under homeostatic conditions, proinflammatory cytokine responses necessary for host immune defense are balanced by anti-inflammatory responses to protect the host from injury that results from unregulated inflammation. When the system is continually challenged, as in persistent viral and bacterial infections or immune dysregulation in autoimmune diseases, a chronic proinflammatory response occurs. For example, dysregulation of IL-1 cytokine signaling is associated with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriasis ( ). Aberrations in the IL-6/IL-12 cytokines likewise result in IBD and RA, as well as systemic lupus erythematosus (SLE), asthma, and Castleman disease ( ; ). Dysregulation of the IFN response is associated with SLE, Sjögren syndrome, systemic sclerosis, myositis, and RA ( ). IL-17A has been linked to many autoimmune disorders, including IBD, RA, and multiple sclerosis (MS), as well as certain cancers ( ). IL-18 is linked to RA and Crohn disease (CD) ( ). IL-5 and IL-13 play a role in allergic asthma. IL-7, IL-9, and other inflammatory cytokines are likewise believed to play causative roles in autoimmune diseases, whereas the anti-inflammatory cytokine IL-10 appears to play a protective role ( ). Patients with chronic infections and/or autoimmune diseases also have an increased risk for concomitant osteoporosis, as RANKL expression—and, therefore, bone resorption—is upregulated by proinflammatory cytokines, including IL-1, IL-6, IL-11, and IL-17, and TNF-α ( ). Even in acute inflammatory diseases such as sepsis, there is dysregulation of the inflammatory cytokine network, including IL-6, IL-8, and IL-10 ( ).

Dysfunction of cytokine receptors also contributes to disease pathologies. Mutations that later affect binding/function of the γ _c receptors or their associated JAK3 kinase can significantly limit the activity of the cytokines that signal through this pathway and can lead to severe combined immunodeficiency (SCID) diseases ( ). Mutations that impact the function of JAK2 kinase are correlated with hematologic malignancies, particularly myeloproliferative neoplasms ( ). Overexpression or mutations that impact function of receptor tyrosine kinases (RTKs) are linked to cancers, atherosclerosis, bone disorders, and diabetes (Kazi et al., 2014). The IL-20R cytokines, including IL-19, IL-20, and IL-24, all signal through the IL-20RA/IL-20RB receptor complex, which has been suggested to be involved in regulating autoimmune diseases such as RA, IBD, and MS ( ; ; ; ).