Katrin Witte

IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not

Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-γ nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-γ and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-α potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations.

Biology of interleukin-22

Interleukin (IL)-22 is a member of the IL-10 family of cytokines and represents an important effector molecule of activated Th22, Th1, and Th17 cells, as well as Tc-cell subsets, γδ T cells, natural killer (NK), and NKT cells. IL-22 mediates its effects via a heterodimeric transmembrane receptor complex consisting of IL-22R1 and IL-10R2 and subsequent Janus kinase–signal transducers and activators of transcription (JAK–STAT) signaling pathways including Jak1, Tyk2, and STAT3. Whereas in some aspects, IL-22 acts synergistically with tumor necrosis factor-α, IL-1β, or IL-17, most functions of IL-22 are unique. Importantly, IL-22 does not serve the communication between immune cells. It mainly acts on epithelial cells and hepatocytes, where it favors the antimicrobial defense, regeneration, and protection against damage and induces acute phase reactants and some chemokines. This chapter illuminates in detail the properties of IL-22 with respect to its gene, protein structure, cellular sources, receptors, target cells, biological effects, and, finally, its role in chronic inflammatory diseases, tumors, and infection.

Interleukin (IL)-19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs

Abstract:  Due to their structural similarity, interleukin (IL)‐19, IL‐20, IL‐22, IL‐24 and IL‐26 were combined with IL‐10 in the so‐called IL‐10 family. To expand the knowledge on IL‐19, IL‐20 and IL‐24, we systematically and quantitatively analysed the expression of these mediators and their receptor chains in vitro and in vivo under various conditions and in comparison with other IL‐10 family members. In vitro, IL‐19, IL‐20 and IL‐24 were produced not only by activated immune cells, particularly monocytes, but also to a similar extent by keratinocytes. IL‐1β increased the expression of these mediators 1000‐fold (IL‐19) and 10‐fold (IL‐20 and IL‐24) in keratinocytes. In vivo, these cytokines were expressed preferentially in inflamed tissues. The absence of either R1 chain for the two types of receptor complexes for these cytokines (IL‐20R1/IL‐20R2 and IL‐22R1/IL‐20R2) on immune cells implies that they cannot act on these cells. In fact, IL‐19, IL‐20 and IL‐24 did not induce activation of signal transducer and activator of transcription (STAT) molecules in immune cells. Instead, several tissues, particularly the skin, tissues from the reproductive and respiratory systems, and various glands appeared to be the main targets of these mediators. Keratinocytes expressed both receptor complexes; however, the expression of IL‐22R1 was 10 times higher than that of IL‐20R1. Interferon‐γ further increased the expression of IL‐22R1 and decreased that of IL‐20R1, suggesting that under T1 cytokine conditions these mediators primarily affect keratinocytes via the IL‐22R1/IL‐20R2 complex. In summary, these data support the notion that IL‐19, IL‐20 and IL‐24 are distinct from classical ILs and constitute a separate subfamily of mediators within the IL‐10 family.

Interleukin-22: A cytokine produced by T, NK and NKT cell subsets, with importance in the innate immune defense and tissue protection

Interleukin (IL)-22 is a member of the IL-10 cytokine family that is produced by special immune cell populations, including Th22, Th1, and Th17 cells, classical and non-classical (NK-22) NK cells, NKT cells, and lymphoid tissue inducer cells. This cytokine does not influence cells of the hematopoietic lineage. Instead, its target cells are certain tissue cells from the skin, liver and kidney, and from organs of the respiratory and gastrointestinal systems. The main biological role of IL-22 includes the increase of innate immunity, protection from damage, and enhancement of regeneration. IL-22 can play either a protective or a pathogenic role in chronic inflammatory diseases depending on the nature of the affected tissue and the local cytokine milieu. This review highlights the primary effects of IL-22 on its target cells, its role in the defense against infections, in tumorigenesis, in inflammatory diseases and allergy as well as the potential of the therapeutic modulation of IL-22 action.

Despite IFN-|[lambda]| receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

Interferon (IFN)-λ1, -2 and -3 (also designated as interleukin (IL)-29, IL-28α and IL-28β) represent a new subfamily within the class II cytokine family. They show type I IFN-like antiviral and cytostatic activities in affected cells forming the basis for IFN-λ1 therapy currently under development for hepatitis C infection. However, many aspects of IFN-λs are still unknown. This study aimed at identifying the target cells of IFN-λs within the immune system and the skin. Among skin cell populations, keratinocytes and melanocytes, but not fibroblasts, endothelial cells or subcutaneous adipocytes turned out to be targets. In contrast to these target cells, blood immune cell populations did not clearly respond to even high concentrations of these cytokines, despite an IFN-λ receptor expression. Interestingly, immune cells expressed high levels of a short IFN-λ receptor splice variant (sIFN-λR1/sIL-28R1). Its characterization revealed a secreted, glycosylated protein that binds IFN-λ1 with a moderate affinity (KD 73 nM) and was able to inhibit IFN-λ1 effects. Our study suggests that IFN-λ therapy should be suited for patients with verrucae, melanomas and non-melanoma skin cancers, apart from patients with viral hepatitis, and would not be accompanied by immune-mediated complications known from type I IFN application.

The Th17 cytokine IL‐22 induces IL‐20 production in keratinocytes: A novel immunological cascade with potential relevance in psoriasis

Psoriasis is a common chronic skin disease. Recent studies demonstrated that IL‐20 and IL‐22, cytokines produced by keratinocytes and T cells, respectively, both inhibit keratinocyte terminal differentiation and induce psoriasis‐like epidermis alterations. Here, we investigated the relationship between these mediators. Although IL‐20 was not able to regulate IL‐22 production, IL‐22 induced IL‐20 mRNA and protein in human keratinocytes. However, IL‐22 had only a minimal effect, if any, on IL‐19 and IL‐26. Cutaneous IL‐20 was also elevated in mice following IL‐22 application. Accordingly, some of IL‐22s effects on differentiation‐regulating genes were partially mediated by an endogenous, secreted protein and attenuated by anti‐IL‐20 Ab. Like IL‐22, IL‐17A and TNF‐α induced IL‐20 in keratinocytes, whereas IFN‐γ and IL‐20 itself did not. Furthermore, IL‐17A and TNF‐α individually strengthened the IL‐22‐induced IL‐20 production. In lesional skin of psoriasis patients, highly elevated IL‐20 levels strongly correlated with IL‐22, and to a lesser extent, with IL‐17A and TNF‐α. As previously shown for IL‐22, IL‐20 blood levels correlated with the disease severity, although with a lower significance. This study demonstrates that a T‐cell mediator induces a tissue cell mediator with similar effects to its own and therefore suggests the existence of a novel type of pathogenetic cascade.

Maturing dendritic cells are an important source of IL-29 and IL-20 that may cooperatively increase the innate immunity of keratinocytes.

IL‐19, IL‐20, IL‐22, IL‐24, IL‐26, IL‐28, and IL‐29 are new members of the IL‐10 interferon family. Monocytes are well‐known sources of IL‐19, IL‐20, and IL‐24. We demonstrated here that monocytes also expressed IL‐29, and monocyte differentiation into macrophages (Mφ) or dendritic cells (DCs) strongly changed their production capacity of these cytokines. Maturation of DCs with bacterial stimuli induced high expression of IL‐28/IL‐29 and IL‐20. Simulated T cell interaction and inflammatory cytokines induced IL‐29 and IL‐20 in maturing DCs, respectively. Compared with monocytes, DCs expressed only minimal IL‐19 levels and no IL‐24. The differentiation of monocytes into Mφ reduced their IL‐19 and terminated their IL‐20, IL‐24, and IL‐29 production capacity. Like monocytes, neither Mφ nor DCs expressed IL‐22 or IL‐26. The importance of maturing DCs as a source of IL‐28/IL‐29 was supported by the much higher mRNA levels of these mediators in maturing DCs compared with those in CMV‐infected fibroblasts, and the presence of IL‐28 in lymph nodes but not in liver of lipopolysaccharide‐injected mice. IL‐19, IL‐20, IL‐22, IL‐24, and IL‐26 do not seem to affect Mφ or DCs as deduced from the lack of corresponding receptor chains. The significance of IL‐20 and IL‐28/IL‐29 coexpression in maturing DCs may lie in the broadly amplified innate immunity in neighboring tissue cells like keratinocytes. In fact, IL‐20 induced the expression of antimicrobial proteins, whereas IL‐28/IL‐29 enhanced the expression of toll‐like receptors (TLRs) and the response to TLR ligands. However, the strongest response to TLR2 and TLR3 activation showed keratinocytes in the simultaneous presence of IL‐20 and IL‐29.

Deficiency of IL-22 Contributes to a Chronic Inflammatory Disease: Pathogenetic Mechanisms in Acne Inversa

Overexpression of the T cell cytokine IL-22 is linked to the development of some chronic diseases, but little is known about IL-22 deficiency in humans. As demonstrated in this study, acne inversa (AI; also designated as Hidradenitis suppurativa) lesions show a relative deficiency of IL-22 and IL-20, but not of IL-17A, IL-26, IFN-γ, IL-24, or IL-1β. Moreover, AI lesions had reduced expression of membranous IL-22 and IL-20 receptors and increased expression of the natural IL-22 inhibitor, IL-22 binding protein. AI is a chronic inflammatory skin disease with prevalence up to 4% of the population and in which cutaneous bacterial persistence represents an important pathogenetic factor. Accordingly, we also found a relative deficiency of antimicrobial proteins (AMPs) in AI lesions and a positive correlation between lesional IL-22 and IL-20 versus AMP levels. IL-22, like its tissue cell downstream mediator IL-20, upregulated AMPs in reconstituted human epidermis and was critical for increased AMP levels under inflammatory conditions. The relative IL-22 deficiency in AI was not linked to lesional T cell numbers or Th22/Th1/Th17 subset markers and -inducing cytokines. However, IL-10 was highly expressed in AI lesions and correlated negatively with IL-22 expression. Moreover, IL-10 inhibited IL-22 but not IL-17 production in vitro. The IL-10 overexpression, in turn, was not associated with an elevated presence of regulatory T cells but with the enhanced presence of an IL-10–inducing cytokine. We conclude that IL-22 deficiency may contribute to the pathogenesis of certain chronic disorders as postulated in this paper for AI.

IL-28A, IL-28B, and IL-29: Promising cytokines with type I interferon-like properties

IL-28A, IL-28B and IL-29 (also designated type III interferons) constitute a new subfamily within the IL-10-interferon family. They are produced by virtually any nucleated cell type, particularly dendritic cells, following viral infection or activation with bacterial components, and mediate their effects via the IL-28R1/IL-10R2 receptor complex. Although IL-28/IL-29 are closer to the IL-10-related cytokines in terms of gene structure, protein structure, and receptor usage, they display type I interferon-like anti-viral and cytostatic activities. Unlike type I interferons, the target cell populations of IL-28/IL-29 are restricted and mainly include epithelial cells and hepatocytes. These properties suggest that IL-28/IL-29 are potential therapeutic alternatives to type I interferons in terms of viral infections and tumors. This review describes the current knowledge about these cytokines.

Is there an interaction between interleukin-10 and interleukin-22?

Interleukin(IL)-10 and IL-22 are structurally related cytokines. Their heterodimeric receptors consist of the cytokine-specific chains IL-10R1 and IL-22R1, respectively, and the common chain IL-10R2. This study focused on the question of whether IL-10 modulates IL-22 effects and vice versa. This question is important because IL-10 and IL-22 exert anti- and proinflammatory effects, respectively, and, as we show here, are simultaneously present in both systemic and local inflammation. The revealed lacking concomitance of IL-10R1 and IL-22R1 on identical cells excluded any possible interaction between IL-10 and IL-22 apart from the competition for IL-10R2. To study this competition, monocytes and hepatocytes were chosen. The dependence of the cytokine action on IL-10R2 was verified. Interestingly, no influence of IL-22 on IL-10 effects was observed. The same was true when IL-22 was used in complex with IL-22-binding protein. Similarly, no influence of IL-10 was found on IL-22 action. This missing competition seemed to be due to a lack of binding between IL-10R2 and the native cytokines in the absence of their corresponding R1 chain. However, IL-10R2 interacted with defined IL-10- and IL-22-derived peptides supporting the hypothesis that cytokine binding to its corresponding R1 chain creates a binding site on this cytokine for IL-10R2.