Structural conservation and functional adaptation of porcine interleukin-10: evolutionary insights and viral mimicry

Interleukin-10 (IL-10) is a key immunoregulatory cytokine essential for anti-inflammatory responses and immune homeostasis. Here, we characterized porcine IL-10 (pIL-10) in comparison with mammalian orthologs and viral IL-10 homologs. Structure-based sequence alignment confirmed conservation of the six-helix bundle, critical for dimerization and receptor binding. Phylogenetic analysis placed pIL-10 close to human and murine IL-10, supporting its translational relevance. The structure of pIL-10 was experimentally determined using X-ray crystallography at a resolution of 2.30 Å. Structural comparison revealed high identity with human IL-10 (74.9 %) and overall structural conservation (RMSD 3.94 Å), with subtle species-specific adaptations in inter-subunit orientation and hydrogen bonding, which may modulate receptor-binding kinetics. Modeling of pIL-10 with porcine IL-10RA/IL-10RB demonstrated conserved binding interfaces and predicted comparable JAK-STAT signaling capacity. Notably, pIL-10 exhibited remarkable similarity to Human gammaherpesvirus 4 (HHV-4) vIL-10 (88.7 % identity, RMSD 1.43 Å), preserving residues essential for dimerization and receptor interaction, consistent with viral structural mimicry. Divergent residues may underlie reduced receptor affinity and signaling potency in vIL-10. Together, these results highlight evolutionary conservation and fine-tuned adaptations of IL-10, establish pigs as a relevant model for human cytokine biology, and provide insights into viral exploitation of IL-10 signaling for immune evasion.