Abstract

Interleukins (ILs) are pleiotropic mediators of immune signaling and represent promising targets for antiviral intervention. Among them, IL‐19 is upregulated in response to viral infections, yet its functional significance and mechanistic basis have been poorly defined. This study identifies an unforeseen antiviral activity of IL‐19. Mechanistically, we demonstrate that IL‐19 signals through the IL‐20RB receptor to drive STAT3 phosphorylation, and this activated IL‐20RB/STAT3 pathway then induces TRIM22 expression, culminating in enhanced IFN‐λ secretion and the direct suppression of viral replication. Importantly, despite significantly curtailing HSV‐1 replication in murine brain and lung tissues, IL‐19 administration failed to confer a survival benefit, an effect attributable to aggravated pulmonary inflammation. These findings clarify IL‐19 as a dual‐function cytokine with both protective antiviral and detrimental proinflammatory properties, illustrating the intricate immunomodulatory functions of cytokines during viral infections.