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Publication Abstract from PubMed

Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Ralpha form a composite surface to engage the shared signaling receptor IL-10Rbeta, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rbeta binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8(+) T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.

Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10.,Saxton RA, Tsutsumi N, Su LL, Abhiraman GC, Mohan K, Henneberg LT, Aduri NG, Gati C, Garcia KC Science. 2021 Mar 19;371(6535):eabc8433. doi: 10.1126/science.abc8433. PMID:33737461^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.