Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 5, Issue 3, 2006

Cytokines are key mediators of the immune system,playing a major role in health and disease. Their crucial importance in host defense, hematopoiesis, inflammation,autoimmunity, tumor and other diseases became obvious over the last two to three decades. Today, targeting components of the cytokine network represents a promising new therapeutic approach, which includes both strategies for antagonizing cytokine action as well the application of recombinant cytokines. Impressive examples are the antagonization of tumor necrosis factor (TNF)-alpha, which represents a breakthrough for the therapy of several inflammatory and autoimmune diseases, the interferon-alpha application, which improved therapy for several tumors, the interferon-beta therapy in patients with multiple sclerosis, the erythropoietin substitution in patients with kidney insufficiency, and the granulocyte-monocyte colony stimulating factor (GM-CSF) application in patients with immune deficiency [1-4]. Intervening into the cytokine network is already well established by using ‘biologicals’ i.e. recombinant proteins including cytokines, neutralizing anti-cytokines and antireceptor antibodies, soluble receptors and various fusion proteins. Novel small molecule approaches may either mimic the cytokine effects, inhibit the cytokine function, or modulate the cytokine expression, but are further down the road.Targeting of cytokines has contributed to the symptom-free life of thousands of patients and has even saved many lives to date. Currently, it is a billion dollar industry and this market will most likely continue to grow in the upcoming years. With the remarkable potential of cytokines in mind, it is no surprise that the discovery of novel cytokines significantly raises the interest of basic and applied research scientists in academia as well as in pharmaceutical companies. Their discoveries trigger questions particularly regarding their biological functions (such as whether they play an important role in disease) and their 'mode of action'. Many cytokines, discovered in the last few years, were delegated to the so-called IL-10 family [5]. Although IL-10 has beenknown since 1989, this family has only recently grown to be comprised of eight additional mediators, namely of IL-19, IL-20, IL-22, IL-24, IL-26, IL-28-alpha, IL-28-beta, and IL- 29 [6]. Interestingly, these cytokines were not grouped in a family based on similar biological effects but rather due to three other reasons: i) they show a similar amino acid sequence and secondary structure, ii) their genes have similar structures and are genomically clustered, and iii) these cytokines bind to receptor complexes composed of two different members of the cytokine receptor family class II. IL-10 is primarily an important immunosuppressive and anti-inflammatory cytokine in humans [7]. As far as the biological effects of the new members of the IL-10 family are known, these novel mediators do not appear to share IL-10's function. However, the current knowledge lets us assume that at least three of the new members also represent promising therapeutic targets. In fact, application of IL-24 is a possible new and potentially effective therapy for eliminating tumors [8]. Moreover, inhibition of the effects of IL- 20 and IL-22 may lead to the improvement of chronic skin diseases [9-11]. The possible therapeutic potential of influencing the effects of IL-20, IL-22, and IL-24 in addition to the contribution of expanding our knowledge on the immune system makes researching the biology of the IL-10 family members both very interesting and important.The purpose of this hot-topic issue is to review the current knowledge with regard to these important immune mediators and their receptors. Top experts contributed chapters for each of the IL-10 family members and their receptors.Thus, this hot-topic issue forms a comprehensive, state-ofthe-art volume giving a valuable overview. REFERENCES [1] Asadullah, K.; Sterry, W.; Trefzer, U. Exp. Dermatol. 2002, 11, 97- 106. [2] Disis, M.L. Oncology (Williston Park), 2005, 19, 5-9. [3] Henry, D.H.; Bowers, P.; Romano, M.T.; Provenzano, R. Arch Intern. Med., 2004, 164, 262-276. [4] Schottelius, A.J.; Moldawer, L.L.; Dinarello, C.A.; Asadullah, K.;Sterry, W.; Edwards, C.K., 3rd. Exp. Dermatol., 2004, 13, 193-222. [5] Volk, H.; Asadullah, K.; Gallagher, G.; Sabat, R.; Grutz, G. Trends Immunol., 2001, 22, 414-417. [6] Pestka, S.; Krause, C.D.; Sarkar, D.; Walter, M.R.; Shi, Y.; Fisher, P.B. Annu Rev. Immunol., 2004, 22, 929-979. [7] Moore, K.W.; de Waal Malefyt, R.; Coffman, R.L.; O'Garra, A.Annu. Rev. Immunol., 2001, 19, 683-765. [8] Sauane, M.; Gopalkrishnan, R.V.; Sarkar, D.; Su, Z.Z.; Lebedeva,I.V.; Dent, P.; Pestka, S.; Fisher, P.B. Cytokine Growth Factor Rev., 2003, 14, 35-51......

The interleukin-10 (IL-10) family of cytokines includes IL-10, its viral homologs, and eight cellular cytokines: IL-19, IL-20, IL-22, IL-24, IL-26, IFN-λ1, IFN-λ2, and IFN-λ3. Cellular homologs use for signaling five recently discovered membrane-bound receptors: three long receptor chains (IL-20R1, IL-22R1, and IFN-λR) and two short receptor chains (IL-20R2 and IL-10R2). Signal transduction is initiated when cytokine binds two receptor chains, one long and one short, forming a ternary complex. Based on the analysis of known structures of ternary and binary complexes, a homology model of the structure of the ternary complex of IL-10/sIL-10R1/sIL-10R2 has been generated. The structure agrees well with all published experimental data, including the crystal structure of the binary IL-10/sIL-10R1 complex and data of peptide scans, mapping the sIL-10R2 binding site. sIL-10R1, sIL-10R2, and inter-receptor interface sites show that most of the intermolecular interactions have a polar nature, although hydrophobic interactions constituting between 20% and 35% from the total number of interactions are also important. Putative complexes of other cytokines of the IL-10 family and the role of glycosylation in ligand/receptor interactions and how it affects biological activity are also discussed.

The interleukin (IL)-10 family of cytokines comprising IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28α, IL- 28β, and IL-29 uses receptors of the cytokine receptor family class 2. Here we review the current knowledge about IL-22 receptor-α2 (IL-22Rα2) which is the first known soluble receptor of that cytokine family. The human IL-22Rα2-encoding gene includes seven exons and is located on chromosome 6 between the genes for interferon-γ receptor-1 and IL-20 receptor- 1. The products of this gene are three different mRNA splice variants. The genes for the mouse and rat IL-22Rα2 have a very similar genomic location and structure to those in humans, although they lack the human exon 4 counterpart and produce only one variant which corresponds to the human variant 2. Irrespective of the species and splice variant, IL- 22Rα2 lacks any sequence for a transmembrane or an intracellular part, and is a secreted protein. It is particularly expressed in the placenta, the mammary glands, and the lymph nodes but also in the gastrointestinal system, the lungs, the skin, and other lymphatic organs. It seems, however, that the variants 3 and 1 are more restricted in their expression. Variant 2 binds to and inhibits the activity of IL-22 in vitro, whereas the specificity of variants 3 and 1 has not been identified. The discovery of IL-22Rα2 represents a first step towards understanding the regulatory network regarding the action of IL-22 and perhaps of other members of the IL-10 family. It also may open up new ways for targeting the action of these cytokines for therapeutic interests.

Interleukin (IL)-10, initially described as cytokine synthesis inhibitory factor, is a pleotropic cytokine produced by many cell populations. Its main biological functions appear to be quite diverse: on the one hand it is involved in the limitation and termination of inflammatory responses and the regulation of differentiation and proliferation of several immune cells, and on the other hand it mediates immunostimulatory properties that support the elimination of infectious and non-infectious particles with limited inflammation. Numerous investigations, including expression analyses in patients, and both in vitro and in vivo studies suggest a major physiological and pathophysiological impact of IL-10. Activation of the neuro-endocrine axis following acute stress reactions leads to systemic IL-10 release, preventing hyperinflammatory reactions. IL-10 is overexpressed in many solid tumors and lymphomas and considered to promote further tumor development. In contrast, a relative IL-10 deficiency has been observed and is regarded to be of pathophysiological relevance in certain inflammatory disorders characterized by a type 1 cytokine pattern such as psoriasis. Recombinant human IL-10 has been tested in several clinical trials including rheumatoid arthritis, inflammatory bowel disease, psoriasis, organ transplantation, and hepatitis C. The results are heterogeneous and give new insight into the immunobiology of IL-10. However, further investigations would be desirable to better determine the effect/side effect profile as well as the best first line target indication and optimal therapeutic regimen.

Interleukin(IL) -19 is a member of the recently described IL-10 family of cytokines. Based on the genomic localization of its gene, its structure, conserved amino acids, cellular sources and receptor, IL-19 forms a subfamily with IL- 20 and IL-24. The IL-19-encoding gene comprises seven exons and is located on chromosome 1. Secreted IL-19 is composed of 159 amino acids that form an α-helical structure. IL-19 is produced by activated monocytes, and to a lesser extent, by B cells. As known so far, IL-19 functions through a receptor complex composed of IL-20R1 and IL-20R2, which is also utilized by IL-20 and IL-24. High levels of both receptor chains are present in several stromal tissues including the skin, lungs, and tissues from the reproductive organs. However, no expression is found in any immune cell population. Nonetheless, all effects of IL-19 described so far concern immune cells. Such conflicting data may be due to the existence of an additional (so far undiscovered) receptor complex for IL-19, or to the ability of the known IL-19 receptor to mediate its effects when present on the cell surface at a very low density. IL-19 has been shown to enhance the production of Th2 cytokines in T cells. Furthermore, it induced IL-10 expression in monocytes. Apart from the implied role for IL-19 in atopic and allergic responses and disorders, it also seems to be involved in the pathogenesis of the Th1-type skin disease psoriasis. IL-19 therefore represents an exciting new cytokine with immunoregulatory functions.

IL-20 is a member of the IL-10 family of cytokines that also includes IL-10, IL-19, IL-22, IL-24, and IL-26 as well as a number of viral homologs. Keratinocytes and monocytes in states of activation can produce IL-20. It transmits signals via two different cell-surface receptor complexes resulting in the activation of STAT3 in keratinocytes and other epithelial cells. Thus it appears to be primarily an inducible autocrine and paracrine factor that regulates proliferation and differentiation of keratinocytes in the context of inflammation. Several findings indicate that IL-20 mediates the hyperproliferation of keratinocytes associated with cutaneous inflammation. As such it is likely to have a central role in inflammatory skin diseases such as psoriasis and eczema. IL-20 also promotes the expansion of multipotential hematopoietic progenitor cells indicating a role beyond the response of epithelial cells to inflammation. Increased understanding of the biology of IL-20 may provide novel opportunities for diagnostic methods and therapeutic intervention.

Originally identified as a gene specifically induced by IL-9 in a mouse T cell lymphoma, IL-22 is mainly produced by TH1 cells or by activated T cells. Human IL-22, which shares 79% amino acid identity with its mouse orthologue and 25% with IL-10 is encoded by a single copy gene and located on chromosome 12, close to the IFNγ gene, whereas the murine IL-22 gene is located on chromosome 10 and is duplicated in some mouse strains. Structurally, IL-22 appears to be a monomer composed of six alpha helices, whose organization is reminiscent of the helices of the IL-10 dimer. Despite its structural relationship with IL-10, IL-22 exerts completely different activities, acting mainly on non hematopoietic cells, such as epithelial cells from lung and colon, hepatocytes and keratinocytes. IL-22 might therefore be involved in inflammatory processes, at least in liver and skin. IL-22 exerts its activity via a complex formed by IL-10Rβ and IL-22R, associated with Tyk2 and Jak1, respectively. The main signaling pathways triggered by IL-22 involve STAT-1, - 3, -5 and the ERK, JNK and p38 MAPKinases. Beside its transmembrane receptor, IL-22 also binds to a soluble receptor, called IL-22BP. This soluble receptor turns out to be a natural antagonist of IL-22 biological activities at least in vitro.

Developing effective and safe therapies for cancer continues to be a primary objective of both basic researchers and clinicians. However, despite evidence of progress in treating specific tumors, in many instances, especially in the context of metastasis, no effective therapies are available. A focus of our laboratories is to develop improved cancer therapeutics that exploit differences in signaling pathways and gene expression in tumor versus normal cells. An approach, which we have pioneered, is the use of 'differentiation therapy' combined with subtraction hybridization, DISH (differentiation induction subtraction hybridization), to define genes that are relevant to cancer growth control, differentiation and apoptosis. Application of DISH to human melanoma cells permitted the cloning of melanoma differentiation associated (mda) genes that display elevated expression as a function of induction of terminal differentiation and loss of tumorigenic potential in cancer cells. One mda gene, mda-7, has emerged as a potential therapeutic for cancer because of its unique ability to selectively induce apoptosis in cancer cells, without affecting normal cells. Based on structure, location and properties, mda-7, a cytokine belonging to the IL-10 family, is now designated as IL-24. mda-7/IL-24 exhibits multiple levels of anti-cancer effects that include inhibition of angiogenesis, radiosensitization and potent antitumor bystander activities. As a cytokine it also demonstrates immunostimulatory properties. An adenovirus expressing mda-7/IL- 24, INGN 241, has entered the clinic and been shown to be safe and display significant activity toward solid tumors, including melanoma, in a Phase I clinical trial. We presently provide a brief overview of mda-7/IL-24.

Interleukin-26 (IL-26) belongs to the family of cellular cytokines which share sequence homology with IL-10, however, without functional conservation. The il-26 gene is situated on the human chromosome 12q15 in close neighbourhood to the genes for the related T-cellular cytokines interferon-γ (IFN-γ) and IL-22. il-26 was discovered due to its overexpression in T cells after growth transformation with herpesvirus saimiri. IL-26 is produced by activated T cells, forms homodimers, and acts on epithelial target cells such as colon carcinoma cells or keratinocytes. Presumably due to its positive net charge, IL-26 adheres to glycosaminoglycans on cell surfaces. Stimulation with IL-26 results in the phosphorylation and activation of the transcription factors STAT1 and STAT3 and in the induction of CD54 surface expression and secretion of cytokines such as IL-8 and IL-10. These effects are mediated by an IL-26-specific receptor complex consisting of IL-20R1 and IL-10R2. Thus, IL-26 appears to be a rather proinflammatory and cell-surface associated cytokine linking local T-cell activation with epithelial functions.

IFN-λs or type III IFNs are also known as IL-28/29. This group of cytokines is the latest addition to the family of cytokines that signal through receptors of the class II cytokine receptor family (CRF2). Although IFN-λs and IFN-α/β (type I IFNs) utilize distinct receptor complexes for signaling, type I and type III IFNs activate the same intracellular signaling pathway and many similar biological activities, including the ability to induce antiviral state in cells. Consistent with their antiviral activity, the expression of IFN-λ mRNAs is inducible by viral an infections. Therefore, IFN-λs functionally resemble type I IFNs, supporting their designation as IFNs. However, IFN- λs also share several common features with cytokines of the IL-10 family that includes IL-19, IL-20, IL-22, IL-24 and IL-26. Their genes have a similar intron-exon structure, they share some sequence homology, and most likely they share a similar structural organization. IFN-λs also share a common receptor subunit, IL-10R2, with IL-10, IL- 22 and IL-26. However, the ligand-binding chain, IFN-λR1, is a unique component of the IFN-λ receptor complex. Although the relative importance of the IFN-λs remains to be fully determined, recent experiments demonstrate their strong potential as antiviral and antitumor therapeutics.