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Targeting IL-10 Family Cytokines for the Treatment of Human Diseases.

ABSTRACT: Members of the interleukin (IL)-10 family of cytokines play important roles in regulating immune responses during host defense but also in autoimmune disorders, inflammatory diseases, and cancer. Although IL-10 itself primarily acts on leukocytes and has potent immunosuppressive functions, other family members preferentially target nonimmune compartments, such as tissue epithelial cells, where they elicit innate defense mechanisms to control viral, bacterial, and fungal infections, protect tissue integrity, and promote tissue repair and regeneration. As cytokines are prime drug targets, IL-10 family cytokines provide great opportunities for the treatment of autoimmune diseases, tissue damage, and cancer. Yet no therapy in this space has been approved to date. Here, we summarize the diverse biology of the IL-10 family as it relates to human disease and review past and current strategies and challenges to target IL-10 family cytokines for clinical use.

SUBMITTER: Wang X

PROVIDER: S-EPMC6360861 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Targeting IL-10 Family Cytokines for the Treatment of Human Diseases.

Wang Xiaoting X Wong Kit K Ouyang Wenjun W Rutz Sascha S

Cold Spring Harbor perspectives in biology 20190201 2

Members of the interleukin (IL)-10 family of cytokines play important roles in regulating immune responses during host defense but also in autoimmune disorders, inflammatory diseases, and cancer. Although IL-10 itself primarily acts on leukocytes and has potent immunosuppressive functions, other family members preferentially target nonimmune compartments, such as tissue epithelial cells, where they elicit innate defense mechanisms to control viral, bacterial, and fungal infections, protect tissu ...[more]

PMID: 29038121

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Project description:Interleukin-10 (IL-10) family of cytokines includes a number of its viral homologs and eight cellular cytokines (IL-19, IL-20, IL-22, IL-24, IL-26, IL-28A, IL-28B, and IL-29). The latter three proteins are also known as IFN-?2, IFN-?3, and IFN-?1, and are recognized as type III (or ?) interferons. Most of the cellular homologs of IL-10 are monomeric in solution, whereas IL-10 and its viral homologs are intercalated dimers consisting of two helical bundle domains topologically similar to the monomeric members of the family. A classical four-helix bundle, a signature element of all helical cytokines, is always found as part of the domain of each member of the IL-10 family. The only crystal structures of these cytokine receptors that have been determined to date are for their extracellular domains (ECDs). Each ECD consists of two ?-sandwich domains connected in the middle by a linkage. Signal transduction occurs when a cytokine binds to its two appropriate receptor chains. IL-10 and its viral homologs use the same IL-10 receptor system, whereas the cellular homologs of IL-10 use their own receptors, which in some cases may overlap and be used in different pairwise combinations. The known structures of binary complexes allowed for marking of the receptor binding site, which always includes helix A, loop AB and helix F (IL-10 notations) on the side of a ligand, loops of the N-terminal and C-terminal domains directed toward the ligand, and the interdomain linkage of the ECD. An analysis of the published structures of both the binary and ternary complexes of all helical cytokines allowed for the generation of a model of the signaling complex of IL-10. The receptor binding site I of the high affinity receptor IL-10R1 is exactly the same as in the crystal structure of the binary IL-10/sIL-10R1 complex, whereas the receptor binding site II is located on the surface of the first and the third helices of the four-helix bundle. The receptor/receptor interface, or site III, is formed between the C-terminal domains of IL-10R1 and IL-10R2.

Dataset Information

Targeting IL-10 Family Cytokines for the Treatment of Human Diseases.

Publications

Targeting IL-10 Family Cytokines for the Treatment of Human Diseases.

Similar Datasets

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