The designation IL-1 refers to two structurally distinct proteins, IL-1α and IL-1β that are encoded by different genes but share common receptors (i.e. IL-1R1/IL-1RAcP or IL-1R2/IL-1RAcP receptor complexes) [30]. There is also an endogenous IL-1 receptor antagonist, IL-1Ra, a recombinant form of which has been used therapeutically to treat IL-1-mediated inflammatory diseases [31]. Similar to TNF, IL-1α and IL-1β are considered innate cytokines, playing a key role in promoting local and in some cases, systemic inflammation and immunity. In addition to contributing to homeostatic aspects of cutaneous immunity and inflammation, IL-1 is implicated in the pathogenesis of Still’s disease, pyoderma gangrenosum (PG), Behçet’s disease, hidradenitis suppurativa (HS) and a number of autoinflammatory diseases. Importantly, IL-1 blockade can be an effective therapy for these diseases [32–34]. Host defense against bacterial pathogens is also mediated by IL-1, as are various aspects of keratinocyte proliferation, differentiation and function (see also Chap. 16) [35–37].

Keratinocytes and other epithelial cell types constitutively produce IL-1α [38]. Unlike IL-1β and most other cytokines, IL-1α is synthesized as a precursor containing a nuclear localization sequence allowing IL-1α to traffic into the nucleus, bind chromatin and regulate transcription [29]. Cellular damage or necrosis promotes release of IL-1α into the local milieu thereby promoting local (neutrophil-mediated) inflammation; as such IL-1α is classified as an alarmin. In contrast, IL-1α remains tightly bound to chromatin during apoptosis, thus restricting inflammation [29].

The disparate effects of IL-1β, compared to IL-1α, are largely a function of differences in cellular processing and cellular sources rather than differences in signaling pathways used by these cytokines [29, 38]. Sources of IL-1β include monocytes, macrophages and dendritic cells and keratinocytes [30]. Like IL-1α, IL-1β is synthesized as a precursor. Unlike IL-1α, production and release of the active form of IL-1β is a highly regulated process mediated by an intracellular complex known as the inflammasome (Fig. 15.3). Production of IL-1β begins with transcription of the IL1B gene and synthesis of Pro-IL-1β. Multiple stimuli (referred to as signal 1) promote IL1B transcription (e.g. TNF, TLR ligands and IL-1) [29]. Unlike IL-1α, the IL-1β precursor (Pro-IL-1β) does not activate IL-1 receptors. Instead, Pro-IL-1β must first undergo proteolysis to generate mature IL-1β [39]. Proteolysis of Pro-IL-1β is performed by caspase-1, which itself must first undergo proteolytic cleavage by the inflammasome. Stimuli that trigger inflammasome activation (referred to here as signal 2) include DAMPs like ATP, pore forming bacterial toxins and others [36]. Upon activation, the inflammasome cleaves procaspase-1 to caspase-1; caspase-1 in turn cleaves Pro-IL-1β generating IL-1β, which is then secreted (Fig. 15.3).

Gain of function mutations in genes encoding proteins in inflammasome underlie a number of autoinflammatory diseases with cutaneous manifestations including: pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome as well as the periodic fever syndromes, familial Mediterranean fever (FMF) and cold induced auto-inflammatory syndromes-1 (CIAS-1), like Muckle-Wells syndrome, familial cold urticaria and neonatal-onset multisystem inflammatory disease [40]. In patients with CIAS-1 spectrum disease, periodic fevers result from increased circulating levels of IL-1β acting as a pyrogen, while urticarial eruptions may be due to skin-resident mast cell-derived IL-1β stimulating increased permeability of cutaneous blood vessels [41, 42]. The critical role of IL-1β in autoinflammatory diseases is highlighted by their responsiveness to IL-1-blocking therapeutics [40].

Several key aspects of host defense against cutaneous infections with Staphylococcus aureus are dependent on IL-1 [36]. In this setting, cell wall components from S. aureus (e.g. lipotechoic acid and bacterial peptidoglycan) activate TLR2 on keratinocytes and macrophages stimulating IL-1 production [43]. Keratinocytes in turn produce IL-1α, and lesser amounts of IL-1β, while macrophages primarily produce IL-1β [36]. Activation of IL-1 receptors for IL-1α or IL-1β, then stimulates keratinocyte production of antimicrobial peptides, neutrophil-attracting chemokines and other cytokines, like IL-6. Antimicrobial peptides can directly combat the infection, while chemokines and IL-6 can recruit neutrophils into the skin; notably, IL-1 can also prolong neutrophil survival, further promoting neutrophil-mediated clearance of the infection [36, 44].

Interleukin 33 (IL-33) is a dual function protein that acts as a cytokine and a nuclear factor that may regulate NF-kB-dependent genes [45, 46]. Cellular damage or necrosis releases IL-33 promoting local inflammation; thus IL-33 is an alarmin like IL-1α [47]. Conversely, proteolytic cleavage inactivates IL-33 during apoptosis preventing IL-33-mediated inflammation [48]. The IL-33 receptor is expressed on Th2 cells, innate lymphoid type 2 cells (ILC2), macrophages, mast cells, eosinophils and other cells. Effects of receptor engagement are cell type specific explaining the pleiotropic functions of IL-33 [49]. For example, IL-33 promotes Th2 cell development and cytokine production, mast cell maturation and activation and polarization of macrophage development towards an M2 phenotype [50, 51]. Paradoxically, IL-33 can promote Th1-polarized inflammation via NK and CD8⁺ T cell stimulation [50]. Expression of IL-33 is increased in lesional skin keratinocytes in atopic dermatitis (AD), psoriasis and lichen planus [52, 53]. In AD, IL-33 concentrations are reportedly increased in the peripheral blood of patients with moderate to severe disease and are reduced following effective topical therapy with steroids or calcineurin inhibitors [52, 54]. These results suggest keratinocyte damage or death in AD lesional skin (possibly secondary to scratching the skin) release IL-33 into the circulation, the consequences of which are not defined in this context.

The IL-36 family includes receptor agonists IL-36α, IL-36β and IL-36γ, hereafter referred to as IL-36. The family also includes IL-36Ra, a receptor antagonist [55]. The IL-36 receptor is composed of IL-36R and IL-1RAcP and utilizes signal transduction pathways like that described above for other IL-1 family members. Loss of function mutations in the IL36RN gene (encodes IL-36Ra) cause some familial and sporadic cases of generalized pustular psoriasis and Acrodermatitis Continua of Hallopeau [56, 57]. Loss of IL-36Ra function is thought to lead to unopposed activation of IL-36 signaling.

The IL-36 receptor is expressed on keratinocytes, monocytes and some dendritic cells [55, 58, 59]. Keratinocytes can produce IL-36α, IL-36β, IL-36γ and IL-36Ra [55]. Transcripts encoding IL-36 family, in low abundance under non-inflammatory conditions, are increased under inflammatory conditions as seen in psoriatic lesions or keratinocytes stimulated with TNF, IL-17, or IL-1 [55]. In human keratinocytes, IL-36 stimulates production of chemokines known to attract T cells, neutrophils and macrophages [58]. In contrast, stimulation of monocytes and myeloid dendritic cells with IL-36 triggers IL-1β and IL-6 production and increased proportions of cells expressing the co-stimulatory molecule CD86 and MHC class II [58]. These observations suggest IL-36 family members are important mediators of inflammation in the skin. Consistent with results from genetic studies suggesting a role for IL-36 in psoriasis pathogenesis, IL-36 is reported to promote psoriasiform inflammation in mice [55–59]. Integrating our current understanding of psoriasis pathogenesis and IL-36 biology, the literature suggests the following role for IL-36 in disease: (1) innate cytokines like IL-1β and TNF as well as IL-17A can stimulate IL-36 production by keratinocytes; (2) IL-36 stimulates keratinocytes to produce multiple chemokines promoting migration of neutrophils, macrophages and T cells in and into the skin; (3) IL-36 stimulates some dendritic cell subsets promoting antigen presentation to T cells and production of innate cytokines like IL-1β and IL-6; (4) IL-1β, TNF, and IL-17A promote various aspects of inflammation in psoriatic lesions and further production of IL-36 by keratinocytes leading to a vicious cycle and persistent disease. Thus, IL-36 or its receptor may become viable therapeutic targets for psoriasis and potentially other dermatologic conditions. Future investigation is still needed to clarify the role of IL-36 in other aspects of normal or pathologic inflammation and immunity in the skin.

Interleukin 2 (IL-2) is the founding member of this family. Activated T cells produce IL-2, as do B cells and some dendritic cells [68–70]. There are two receptor complexes for IL-2, a heterodimer of the β and γ_c chains and a heterotrimer of the high affinity subunit IL-2Rα (i.e. CD25) bound to the β and γ_c chains [71]. While IL-2Rα increases binding affinity for IL-2, the β and γ_c chains regulate signal transduction. Shared usage of β and γ_c chains explains similarities in biologic effects of IL-2 and IL-15, while use of distinct high affinity receptor subunits (i.e. IL-2Rα vs. IL-15Rα) helps explain differences between these cytokines [72].

One or both forms of the IL-2 receptor are expressed on T cells, B cells, NK cells, monocytes and macrophages [71, 73, 74]. In addition to PI3K-Akt and RAS/MAPK signaling, receptor engagement activates JAK1 and JAK3 triggering phosphorylation of STAT1, STAT3 and STAT5. T cell survival and proliferation are important effects of IL-2 during antigen-specific immune responses, as in allergic contact dermatitis [75]. Based on the ability of IL-2 to promote T cell survival and proliferation, recombinant human IL-2 became one of the first FDA-approved immunotherapies for metastatic melanoma [76, 77]. In contrast, an IL-2-diphtheria toxin fusion protein is used to trigger death in cells expressing IL-2Rα; this agent is used to treat some forms of cutaneous T cell lymphoma (CTCL) [78]. Interleukin 2 also regulates peripheral tolerance through effects on regulatory T cells, promotion of Fas-mediated activation-induced cell death of Th cells, and by restraining CD8⁺ T cell responses [79, 80]. Some of the aforementioned immunostimulatory and immunosuppressive effects of IL-2 are lacking in IL-2Rα deficient patients, leading to features of autoimmunity and immunodeficiency as well as cutaneous manifestations including psoriasiform dermatitis and alopecia universalis [81].

Interleukin 4 (IL-4) is a canonical Th2 cytokine produced by Th2 cells, mast cells, basophils and eosinophils [82]. There are two functionally distinct heterodimeric IL-4 receptor complexes. The first (Type I receptor) is specific for IL-4 and is composed of IL-4Rα and γ_c; the second (Type II receptor) binds IL-4 or IL-13 and is composed of IL-4Rα and the IL-13Rα1 [83]. The Type I receptor is expressed on T and B cells, myeloid cells and fibroblasts and acts through JAK1 and JAK3 leading to phosphorylation of STAT3 and STAT6. The Type II receptor is also expressed by myeloid cells and fibroblasts and is selectively expressed on smooth muscle and epithelial cells, including keratinocytes and acts through JAK1, JAK2, JAK3 and TYK2 and activation of STAT3, STAT5 and STAT6 [82–84].

Effects of IL-4 are pleiotropic and cell-type dependent. Depending on the presence or absence of TGF-β, IL-4 can polarize naïve CD4⁺ Th cell differentiation towards Th2 or Th9 lineages; IL-4 can also promote T cell survival (Fig. 15.1) [85, 86]. In B cells, IL-4 promotes survival, B cell receptor and MHC class II expression, and IgE class switching [87–89]. Mast cell survival and proliferation are also promoted by IL-4 [90]. In keratinocytes, IL-4 impairs differentiation, which correlates with impaired epidermal barrier function in vivo [91–93]. Dendritic cell maturation and eosinophil chemotaxis are also stimulated by IL-4 [94, 95].

Interleukin 13 is another Th2 cytokine and is produced by Th2 cells, ILC2, mast cells, eosinophils, basophils and NKT cells [96, 97]. The Type II receptor (shared with IL-4), mediates many of the overlapping biologic effects of IL-4 and IL-13 including IgE class switching, dendritic cell maturation, mast cell activation and eosinophil recruitment [83]. A second receptor, IL-13Rα2, is IL-13-specific and is generally regarded as a decoy receptor; though some IL-13Rα2-specific functions have been demonstrated in mouse models of allergic lung inflammation [83, 98].

The aforementioned functions of IL-4 and IL-13 explain why they are key mediators of allergic inflammation in multiple tissues and are implicated in the pathogenesis of various aspects of atopy, including AD [99]. Both cytokines are detectable in acute and chronic AD lesions and mediate key aspects of AD pathogenesis, epidermal barrier dysfunction and Th2-polarized inflammation. A neutralizing antibody against IL-4Rα that prevents IL-4 and IL-13 signaling is in clinical trials for AD [100].

Interleukin 9 is produced by several Th subsets, most notably Th9 cells, and mast cells; of note Th9 cell development is dependent on IL-4 and TGF-β (Fig. 15.1) [86, 101]. Type I interferons, IL-1, IL-6, IL-10, IL-12, IL-21, IL-25 and LPS promote IL-9 production in relevant cells types [86, 102, 103]. The IL-9 receptor is a heterodimer of IL-9R and γ_c that signals via JAK1 and JAK3 and then, STAT1, STAT3 and STAT5 [86, 104]. This receptor can be expressed on mast cells, Th2 cells, Th17 cells, ILC2, B cells, smooth muscle cells and some epithelial cells [86, 105]. Stimulation with IL-9 promotes mast cell proliferation and production of proteases and a variety of cytokines including IL-1β, IL-5, IL-6, IL-13, TGF-β [106, 107]. This cytokine also promotes Th17 development, ILC2 survival and production of IgE and IgG by B cells [86, 105].

Recently, IL-9 was implicated in the pathogenesis of psoriasis and mouse models of melanoma [108–110]. With respect to psoriasis, Th9 cells were more abundant in psoriatic lesions, suggesting a role in disease [108, 111]. In mouse models of melanoma, IL-9 can exert anti-tumor effects; although the proposed mechanisms underlying these observations varied with one report demonstrating mast cell-dependent anti-tumor effects of IL-9 and another suggesting that IL-9 indirectly promotes effector CD8⁺ T cell recruitment into tumors [109, 110].

Thymic stromal lymphopoietin (TSLP) is included in this section because its receptor is composed of IL-7Rα and a γ_c-like receptor-subunit, TSLPR. In contrast to IL-7, which regulates development, proliferation and/or survival of lymphoid cells, TSLP promotes allergic inflammation in skin and other epithelial surfaces [112–114]. Upon stimulation with TSLP, its receptor activates JAK1 and JAK2 and subsequently, STAT1, STAT3, STAT4, STAT5, and STAT6, which then regulate TSLP target genes [74].

Keratinocytes and dendritic cells can produce TSLP [115]. Production of TSLP by keratinocytes is increased in lesional skin of AD and Netherton syndrome, both of which are characterized by epidermal barrier dysfunction and Th2-polarized inflammation [115, 116] (see also Chap. 22). Interestingly, experimentally induced epidermal barrier disruption and/or injury trigger TSLP production by keratinocytes in normal human skin [117]. In Netherton syndrome and AD, excessive serine protease activity can also stimulate the protease activated receptor 2 and consequently, TSLP production by keratinocytes. Activation of TLR2 signaling in keratinocytes by membrane fragments of S. aureus, a common skin pathogen that also colonizes the skin of patients with AD, can stimulate TSLP production [118]. Inflammatory cytokines can also promote TSLP production by keratinocytes and dendritic cells [114]. Thus, there are multiple potential stimuli to explain the increased production of TSLP by keratinocytes in lesional skin of patients with AD and Netherton syndrome, the downstream consequences of which will be described below.

Dendritic cells, Th2 cells, regulatory T cells, ILC2, mast cells, eosinophils, B cells and NKT cells express the TSLP receptor [114, 119]. Stimulation of dendritic cells with TSLP polarizes naïve T cell differentiation towards Th2 cells and promotes production of the chemokines CCL17 and CCL22, which can act as chemoattractants for Th2 cells. Moreover, stimulation of Th2, ILC2 and mast cells promotes Th2 cytokine production. Several mouse models of AD-like inflammation demonstrate that keratinocyte-derived TSLP production is sufficient to drive allergic inflammation, even in the absence of T cells [120]. Recently, TSLP was shown to directly stimulate sensory neurons in the skin leading to pruritus (itch) in mice injected with recombinant TSLP [121]. These findings indicate TSLP can directly promote allergic inflammation (via actions on leukocytes) and itch (via actions on neurons); both properties of TSLP are likely to be germane to AD pathogenesis. A phase I clinical trial with a humanized TSLP neutralizing antibody has been completed with healthy patients and patients with AD; however the results of these studies are not available at ClinicalTrials.gov.

A variety of cells produce IL-6 including lymphocytes, monocytes, macrophages, fibroblasts, keratinocytes, endothelial cells and others [125]. Stimuli for IL-6 production include PAMPs (e.g. LPS), cytokines (e.g. IL-1, TNF, IL-17) and others. The functional repertoire of IL-6 is extensive with effects on the acute phase response, thermal regulation, angiogenesis, pathologic bone resorption, lipid metabolism and many other physiologic and pathophysiologic processes. However, this section will focus on functions of IL-6 relevant to dermatologic diseases [125].

The IL-6 receptor is composed of gp130 and IL-6R. While gp130 is widely expressed, IL-6R is primarily restricted to lymphocytes, monocytes and neutrophils [125]. Receptor engagement activates JAK3, STAT3, MAPK and PI3K/Akt pathways [127]. A soluble form of the IL-6R subunit (similar to IL-15Rα) can also initiate signaling but the details of this are beyond the scope of this discussion [128]. Effects of IL-6 receptor activation are cell type specific. In B cells, IL-6 stimulates immunoglobulin production and plasma cell differentiation; the role of IL-6 in plasma cell differentiation may be an indirect effect mediated by IL-21 produced by IL-6 stimulated T cells [129]. Other effects of IL-6 on the T cell compartment are promotion of Th17 and follicular helper T cell (Tfh) cell development and suppression of regulatory T cell (Treg) development and function (Fig. 15.1) [130, 131]. As described below, IL-6 also promotes neutrophil accumulation in the skin [125].

While IL-6 can contribute to many normal (e.g. promotion of sterile inflammation after wounding) and pathologic processes in the skin, this section will focus on the roles of IL-6 in cutaneous bacterial infections and psoriasis. As noted earlier, IL-1 is a central mediator of host defense following cutaneous infections with S. aureus. One of the downstream mediators of this host defense mechanism is IL-6, which is produced by keratinocytes and myeloid cells in response to IL-1 [36]. Like IL-1, IL-6 stimulates production of chemokines that attract neutrophils; moreover, IL-6 stimulates endothelial cells to induce expression of adhesion molecules needed for neutrophil migration into the skin from the blood. The Th17 cell subset is thought to be an important source of IL-17A and IL-17F during cutaneous infections and in psoriatic lesions. Differentiation of Th17 cells from naïve T cells is promoted by IL-6, suggesting another, albeit indirect, mechanism whereby IL-6 can contribute to host defense against cutaneous bacterial infections and psoriasis pathogenesis (Fig. 15.1) [36]. For completeness sake, it should be noted that IL-17 producing cell types other than Th17 cells are also implicated in pathogenesis of cutaneous infections and psoriasis pathogenesis and that these populations do not appear to be IL-6 dependent [36, 132].

Like other Th2 cytokines, IL-31 is an important mediator of allergic inflammation and has been implicated in AD pathogenesis (see also Chap. 22) [126]. The Th2 cell subset produces IL-31 in response to IL-4 or IL-33, and mast cells can produce IL-31 upon stimulation with the antimicrobial peptides LL-37 and β-defensins [133, 134]. The IL-31 receptor is expressed on neurons, keratinocytes and some dendritic cell subsets, monocytes and macrophages [126, 135–137]. In contrast to most IL-6 family members, the IL-31 receptor does not utilize gp130; instead it is composed of a gp130-like subunit, IL-31Rα, and the oncostatin M receptor [138]. Receptor engagement activates JAK1, JAK2, STAT1, STAT3, STAT5, PI3K/Akt and MAPK signaling [138]. Like TSLP, IL-31 can directly stimulate neurons and provoke scratching of the skin in mice, suggesting IL-31 can directly induce pruritus (see also Chap. 12) [126, 139]. In vitro studies also suggest IL-31 impairs keratinocyte proliferation and differentiation, which may impair epidermal barrier function [135]. Finally, stimulation of CD1c⁺ dendritic cells with IL-31 promotes production of inflammatory cytokines and chemokines [137].

Pruritus is a characteristic feature of AD; IL-31 and TSLP are proposed to be important triggers for pruritus in this disease (i.e. they are pruritogens). In support of this, IL-31 expression is increased in lesional and nonlesional skin of patients with AD and in lesions of prurigo nodularis [126]. Serum levels of IL-31 are also elevated in AD and correlate with disease severity [140]. Based on the functions mentioned above, it is also possible that IL-31 contributes to pathogenesis via impairment of epidermal barrier function and promotion of cytokine and chemokine production. According to ClinicalTrials.gov, patients are currently being recruited for a phase I clinical trial of an IL-31 blocking antibody in healthy subjects and patients with AD.

Interleukin 10 is one of the prototypic anti-inflammatory cytokines [141]. Multiple cells can produce IL-10 including lymphocytes (T, B & NK cells), macrophages, dendritic cells, mast cells, eosinophils, neutrophils and keratinocytes [141, 148]. The inductive stimuli regulating IL-10 production vary by cell type. In Th2 cells, IL-4 and IL-27 can stimulate IL-10 production; IL-6 and IL-27 can also stimulate IL-10 production by Th1 cells and Th17 cells [149, 150]. In addition to Th cells, several regulatory T cell subsets can produce IL-10; for instance, CD4⁺FoxP3⁺ regulatory T (Treg) cells produce IL-10 in response to IL-2 and IL-4 [151, 152]. Regulatory B cells also produce IL-10 [153]. In macrophages and dendritic cells, TLR (e.g. TLR2, TLR3, TLR4 and TLR9) engagement can also stimulate IL-10 production [154, 155].

The IL-10 receptor is primarily expressed on lymphoid and myeloid cell lineage cells and is composed of IL-10R1 and IL-10R2 [141, 156]. Receptor engagement by an IL-10 homodimer activates JAK1, TYK2, STAT1, STAT3 and STAT5 [157]. Two anti-inflammatory mechanisms by which IL-10 acts include the inhibition of various aspects of antigen presentation by macrophages and dendritic cells and attenuation of cytokine production by T cells [157]. Interestingly, multiple viruses, including Epstein Barr virus and cytomegalovirus produce IL-10 homologs, which are thought to attenuate antiviral immune responses [158]. With respect to dermatologic disease, the anti-inflammatory effects of IL-10 are likely to play a role in regulating many aspects of cutaneous inflammation and immunity. The list of dermatologic diseases in which IL-10 is implicated as a mediator of pathogenesis or a potential therapy is long including multiple infectious, inflammatory, autoimmune and neoplastic conditions [159]. Notably, clinical trials with recombinant IL-10 for psoriasis or wound healing did not show significant benefit [160].

Cellular sources of IL-22 include T cells (e.g. Th17, Th22, γδT cells), NK cells, and a subset of ILC3 [161–165]. Development of IL-22 producing cells and/or production of IL-22 are regulated by cytokines in a cell-type dependent manner. Development of Th17 cells, which produce IL-17 and IL-22, is driven by IL-6, IL-21 and TGF-β; whereas, development of Th22 cells, which produce IL-22 but not IL-17, is stimulated by IL-6 and TNF (Fig. 15.1) [25, 166–169]. Stimulation with IL-23 can induce IL-22 production by some T cell subsets and ILC3 [170–172]. While TGF-β promotes Th17 development, it inhibits IL-22 production by Th17 and Th22 cells [25, 173].

The IL-22 receptor, composed of IL-10R2 and IL-22R, is expressed on keratinocytes and other epithelial cells [141, 156, 174]. Receptor activation signals through JAK1, TYK2, STAT1, STAT3 and STAT5 and MAPK and Akt pathways [141]. In keratinocytes, IL-22 impairs differentiation and promotes proliferation (and thus epidermal hyperplasia) and increases expression of β-defensin 2, β-defensin 3, S100A8 and S100A9, all of which are molecular, cellular, or histologic features of psoriatic lesions [173, 175–177].

Psoriasis, AD and other diseases are mediated, in part, by IL-22 (see also Chap. 21) [23, 178]. In psoriasis and AD, increased levels of IL-22 and IL-22 producing cell subsets are described in lesional skin, and lesion resolution is associated with reduced IL-22 expression [23, 162, 178–186]. In both diseases, IL-22 is thought to act on keratinocytes leading to acanthosis and increased expression of S100A8, S100A9 and other proteins. While IL-22 can promote production of β-defensin 2 and β-defensin 3, expression is higher in psoriatic lesions than in AD; this may be due to Th2 cytokines attenuating expression of these β-defensins in AD [177, 187–189]. According to ClinicalTrials.gov AD patients are being enrolled for a clinical trial using an antibody to IL-22.

Interleukins 19, 20 and 24, hereafter referred to as IL-20 receptor cytokines, are discussed together due to overlapping receptor usage and biologic effects. Keratinocytes and other epithelial cells, monocytes, some T cells and melanocytes can produce one or more IL-20 receptor cytokines; myeloid dendritic cells expressing IL-20 are also present in psoriatic lesions [190–196]. In keratinocytes, IL-1β, IL-17A, IL-22, UVB light and wounding promote IL-20 receptor cytokine production [191, 197–199]. In monocytes, LPS, GM-CSF and TNF stimulate production [141, 196, 200, 201]. Both receptors for these cytokines are expressed by keratinocytes [176, 191]. Receptor engagement activates STAT3 driving keratinocyte proliferation and epidermal hyperplasia [176, 191]. Other effects of one or more of these cytokines on keratinocytes include increased expression of S100A7, as well as TNFA and MRP14 transcripts [176, 202].

Similar to IL-22, IL-20 receptor cytokines are implicated in psoriasis pathogenesis with expression of all three cytokines being increased in lesional skin [191, 196]. These cytokines are thought to contribute to epidermal hyperplasia in psoriatic lesions [176]. Consistent with this idea, local or systemic therapy for psoriasis reduces both epidermal hyperplasia and expression of these cytokines [203, 204]. It is uncertain whether targeting IL-20 receptor cytokines is a viable therapeutic option for psoriasis. According to ClinicalTrials.gov, one clinical trial with an anti-IL-20 blocking antibody was discontinued due to apparent lack of response; however, it is possible that IL-19 or IL-24 activities are sufficiently redundant to compensate despite IL-20 blockade. Paradoxically, IL-20 receptor cytokines were recently shown to exacerbate cutaneous infections with S. aureus in mice [205]. This is attributed to IL-20 receptor-mediated attenuation of IL-1β production, thereby decreasing the frequency of IL-17A producing T cells, which are important for host defense against infections with S. aureus [36, 205, 206]. This suggests the IL-20 receptor may be a viable therapeutic target for management of cutaneous infections with S. aureus.

Interleukin 12 (IL-12p70) is composed of p40 and p35 and expressed by dendritic cells, monocytes, macrophages, B cells and neutrophils [212]. Stimulation of macrophages and dendritic cells with a variety of PAMPs causes IL-12 production [213, 214]. Cytokines (i.e. IFNγ, IL-4 and IL-13) and physical contact with T cells can also promote IL-12 production [215–217]. The IL-12 receptor, composed of IL-12Rβ1 and IL-12Rβ2, is expressed on T and NK cells [207]. Receptor engagement activates JAK2, Tyk2 and STAT4, triggering IFNγ production by T and NK cells [207, 218]. Stimulation of dendritic cells and monocytes with IFNγ can in turn stimulate additional IL-12 production resulting in a positive feedback loop [216]. Interleukin 12 also orchestrates differentiation of naïve T helper cells into Th1 cells, which are key producers of IFNγ (Fig. 15.1) [219, 220]. The ability of microbial products to trigger IL-12 production by dendritic cells and IL-12 to in turn dictate naïve T cell differentiation to Th1 cells is an example how cytokines link innate and adaptive immune responses.

Multiple dermatologic conditions are mediated by IL-12, some of which have been successfully treated with a p40 neutralizing antibody, which blocks both IL-12 and IL-23 [221–227]. As noted above, multiple clinical trials have established the efficacy of this antibody for psoriasis; there are case reports of therapeutic benefit in AD, HS and Behçet’s disease as well [228–230]. Host defense against mycobacterial infections is also critically dependent on IL-12-driven production of IFNγ, as discussed later in this chapter.

Interleukin 23 is a heterodimer of p19 and p40, the latter of which is shared with IL-12 [231]. Dendritic cells and macrophages produce IL-23 following activation of various pattern recognition receptors (e.g. TLR4), cytokine stimulation (e.g. TNF and IL-12) and contact-dependent interactions with T cells [212, 231, 232]. The IL-23 receptor is expressed on Th17 cells, some γδ T cells and ILC3 and is composed of IL-23R, and IL-12Rβ1; receptor engagement signals through JAK2, Tyk2, STAT3 and STAT4 [166, 231, 233–235]. Activation of STAT3 in naïve T cells with specific cytokines (e.g. IL-6) drives Th17 differentiation and IL-23 receptor expression; moreover, IL-23 stimulation further promotes IL-23R expression in these cells [166, 236]. In contrast, the IL-23 receptor is stably expressed on a subset of γδ T cells and is expressed on a subset of ILC3 [235, 237]. In Th17 cells and IL-23R⁺ γδ T cells, IL-23 can promote expansion of these subsets and IL-17 production [166, 235, 236]. Moreover, IL-23 stimulates IL-22 production by IL-23R⁺ ILC3 [237].

Interleukin 23 is implicated in the pathogenesis of psoriasis and many other dermatologic diseases [223, 224, 226, 227, 238–242]. Expression of both IL-23 subunits is increased in psoriatic lesions [238]. Moreover, several IL-23 responsive subsets of IL-17 producing cells are more abundant in psoriatic lesions; IL-17 and IL-22 expression are also increased in lesional skin [235, 237]. As noted, neutralization of p40 and thus IL-12 and IL-23 is an effective therapy for psoriasis. While, both cytokines likely contribute to disease, IL-23 is probably more important as demonstrated by the therapeutic efficacy of an IL-23 neutralizing antibody for psoriasis [243, 244]. In psoriasis, IL-23 is thought to drive IL-17 production; the therapeutic efficacy of IL-17 and IL-17 receptor blocking antibodies in clinical trials (discussed below) for psoriasis further supports the conclusion that IL-23 plays a more dominant role in psoriasis pathogenesis than does IL-12 (see also Chap. 43).

Interleukin 17A, also known as IL-17, activates the same receptor as IL-17F, explaining the similar biologic functions of these cytokines. These cytokines can exist as homodimers or heterodimers of IL-17A and F [245]. Cells that produce IL-17A and/or F include several T cells subsets (i.e. Th17, Tc17 and γδTcells), NKT cells and a subset of ILC3 [165, 253–258] Investigations of IL-17 biology identified Th17 cells, a novel developmentally and functionally distinct population of T helper cells differentiated from naïve T cells stimulated with IL-1β, IL-6, IL-21, IL-23 and/or TGF-β; Th17 cell can produce IL-17A and F (Fig. 15.1) [253, 259]. Activation of the TCR and/or stimulation with IL-1 or IL23 can stimulate IL-17 production by Th17 cells, NKT cells and γδTcells [257, 260–262].

The receptor for IL-17A and F, referred to here as the IL-17 receptor, is a heterodimer of IL-17RA and IL-17RC [263]. T cells, B cells, macrophages, endothelial cells, fibroblasts and epithelial cells, including keratinocytes, express the IL-17 receptor [245]. Receptor engagement in keratinocytes recruits the adaptor protein Act1 and TRAF6 stimulating TAK1-mediated activation of NF-kB and C/EBP and MAPK-mediated activation of AP-1, culminating in transcriptional changes in IL-17 target genes [264–266]. Target genes induced by IL-17 receptor activation include those encoding pro-inflammatory cytokines (TNF, IL-1, IL-6, G-CSF, GM-CSF), chemokines (CXCL1, 3, 5, 6 and 8; CCL2, 7 and 20), antimicrobial peptides/proteins and matrix metalloproteinases [62, 245, 267–269]. Many chemokines produced by IL-17-stimulated keratinocytes recruit neutrophils into the skin, while keratinocyte-derived CCL20 can recruit dendritic cells and CCR6⁺ T cell subsets, including Th17 cells [268].

While IL-17A and F are implicated in the pathogenesis of other dermatologic conditions, this section will focus on the role of these cytokines in psoriasis and cutaneous infections [23, 36, 224, 270–273]. In psoriasis, IL-17 is thought to stimulate keratinocyte-derived chemokine and growth factor production (i.e. G-CSF & GM-CSF) leading to recruitment of neutrophils, T cells (e.g. Th17 cells) and dendritic cells into lesional skin [23]. Cellular sources of IL-17 in psoriasis include Th17 cells, γδT cells, NKT cells and ILC3 [23, 274]. Data from clinical trials suggest neutralizing antibodies to IL-17A and the IL-17 receptor (anti-IL-17RA) will be effective therapies for psoriasis (see also Chap. 43) [210, 275–277].

With respect to cutaneous infections, IL-17A and/or F play important roles in host defense against S. aureus and Candida spp. [36, 273]. As noted, neutrophil influx into the skin, a critical aspect of host defense against S. aureus infections, is regulated by chemokines and growth factors produced by IL-17 stimulated keratinocytes [36]. Host defense against cutaneous Candida spp. infections is also regulated by IL-17A and IL-17F as defective IL-17 signaling can cause chronic mucocutaneous candidiasis (CMC) [273]. In CMC, mutations in IL-17RA and IL-17F have been identified in some patients, while others have mutations that impair development of IL-17 producing T cells or mutations that lead to development of IL-17 neutralizing antibodies [273].