Structural basis for receptor sharing and activation by interleukin-20 receptor-2 (IL-20R2) binding cytokines

Center for Biophysical Sciences, University of Alabama, Birmingham, AL 35294, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2012; 109(31):12704-9. DOI: 10.1073/pnas.1117551109
Source: PubMed


Interleukin 20 (IL-20) is a pleotropic IL-10 family cytokine that protects epithelial surfaces from pathogens. However, dysregulated IL-20 signaling is implicated in several human pathologies including psoriasis, rheumatoid arthritis, atherosclerosis, and osteoporosis. IL-20, and related cytokines IL-19 and IL-24, designated IL-20 subfamily cytokines (IL-20SFCs), induce cellular responses through an IL-20R1/IL-20R2 (type I) receptor heterodimer, whereas IL-20 and IL-24 also signal through the IL-22R1/IL-20R2 (type II) receptor complex. The crystal structure of the IL-20/IL-20R1/IL-20R2 complex reveals how type I and II complexes discriminate cognate from noncognate ligands. The structure also defines how the receptor-cytokine interfaces are affinity tuned to allow distinct signaling through a receptor complex shared by three different ligands. Our results provide unique insights into the complexity of IL-20SFC signaling that may be critical in the design of mechanistic-based inhibitors of IL-20SFC-mediated inflammatory disease.

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Available from: Naomi J Logsdon, Aug 26, 2014
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    • "Based on sequence homology, chromosomal localization, and its functional properties, the mda-7 gene is now categorized as a member of the IL-10 family of cytokines and named IL-24 [18]. IL-24 signals in physiologic condition, triggers via binding to heterodimeric receptors, IL/ 20R1/R2 and IL-22R1/IL20R2 with R1 and R2 subunits [19] [20] [21] [22]. The IL-24 receptor is expressed on the cells of skin, lung, and reproductive tissues which are non-hematopoietic [23]. "
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    ABSTRACT: Hodgkin’s Lymphoma (HL) as a prevalent hematolymphoid malignancy begins in cells of immune system and is characterized by the specific histologic, clinical properties. Abnormality in apoptosis has been recognized as a crucial pathway in its progression. Nowadays, 35-40% of patients in stages III and IV show disease relapse or symptoms of refractory to first-line chemotherapy; therefore, novel treatment strategies are required. As apoptosis inducing is an important mechanism in cancer treatments, novel anticancer molecules to induce programmed cell death are required. The authors present a novel therapeutic approach for HL, with regard to anti-tumoral and immunomodulatory effects of the mda-7/IL-24. This gene, located in human chromosome 1q32-33, has shown tumor suppressor activity in various human malignant cells in, in vitro, in vivo, and even in clinical trial studies. Our hypothesis was designed to evaluate anti- tumoral effects of mda-7/IL-24 in SCID mice model using the adenovirus-based vector. mda-7/IL-24 interestingly has antiangiogenic, immunomodulatory, and bystander antitumoral activities. mda-7/IL-24 can suppress anti-apoptotic Bcl-2 family proteins, and induces GADD family, Bak, Bax, and other pro-apoptosis proteins. This hypothesis suggests that adenovirus vectors expressing mda-7/IL-24 may help for effective immunotherapies of HL.
    Iranian Journal of Medical Hypotheses and Ideas 05/2014; 9(1). DOI:10.1016/j.jmhi.2014.05.002
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    • "It is, however, important to remember that IL-10R2 is a shared chain that is capable of binding several different cytokines (IL-10, IL-22 and IL-26 and the IFNls). The chain is thus, promiscuous, allowing itself to interact with different ligands (Logsdon et al, 2012). "
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    ABSTRACT: The IFNL4 gene is a recently discovered type III interferon, which in a significant fraction of the human population harbours a frameshift mutation abolishing the IFNλ4 ORF. The expression of IFNλ4 is correlated with both poor spontaneous clearance of hepatitis C virus (HCV) and poor response to treatment with type I interferon. Here, we show that the IFNL4 gene encodes an active type III interferon, named IFNλ4, which signals through the IFNλR1 and IL-10R2 receptor chains. Recombinant IFNλ4 is antiviral against both HCV and coronaviruses at levels comparable to IFNλ3. However, the secretion of IFNλ4 is impaired compared to that of IFNλ3, and this impairment is not due to a weak signal peptide, which was previously believed. We found that IFNλ4 gets N-linked glycosylated and that this glycosylation is required for secretion. Nevertheless, this glycosylation is not required for activity. Together, these findings result in the paradox that IFNλ4 is strongly antiviral but a disadvantage during HCV infection.
    The EMBO Journal 10/2013; DOI:10.1038/emboj.2013.232 · 10.43 Impact Factor
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    • "The transcriptional effects of IL-20 family cytokines, therefore, were associated with both increased and decreased expression in psoriasis lesions. Corresponding trends were observed for each of the three cytokines (IL-19, IL-20 and IL-24), consistent with the observation that each cytokine signals through the same IL-20R1/IL-20R2 receptor complex [45]. Although the importance of IL-20 family cytokines in plaque formation is not completely understood, mRNA and protein levels of IL19, IL20 and IL24 are significantly elevated in psoriatic epidermis [46]. "
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    ABSTRACT: Psoriasis lesions are characterized by large-scale shifts in gene expression. Mechanisms that underlie differentially expressed genes (DEGs), however, are not completely understood. We analyzed existing datasets to evaluate genome-wide expression in lesions from 163 psoriasis patients. Our aims were to identify mechanisms that drive differential expression and to characterize heterogeneity among lesions in this large sample. We identified 1233 psoriasis-increased DEGs and 977 psoriasis-decreased DEGs. Increased DEGs were attributed to keratinocyte activity (56%) and infiltration of lesions by T-cells (14%) and macrophages (11%). Decreased DEGs, in contrast, were associated with adipose tissue (63%), epidermis (14%) and dermis (4%). KC/epidermis DEGs were enriched for genes induced by IL-1, IL-17A and IL-20 family cytokines, and were also disproportionately associated with AP-1 binding sites. Among all patients, 50% exhibited a heightened inflammatory signature, with increased expression of genes expressed by T-cells, monocytes and dendritic cells. 66% of patients displayed an IFN-gamma-strong signature, with increased expression of genes induced by IFN-gamma in addition to several other cytokines (e.g., IL-1, IL-17A and TNF). We show that such differences in gene expression can be used to differentiate between etanercept responders and non-responders. Psoriasis DEGs are partly explained by shifts in the cellular composition of psoriasis lesions. Epidermal DEGs, however, may be driven by the activity of AP-1 and cellular responses to IL-1, IL-17A and IL-20 family cytokines. Among patients, we uncovered a range of inflammatory- and cytokine-associated gene expression patterns. Such patterns may provide biomarkers for predicting individual responses to biologic therapy.
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