The present in vitro result showed that IL-38 exhibited profound anti-inflammatory properties in the co-culture of respiratory epithelial cells with macrophages in a dose-dependent manner by inhibiting the production of main cytokines and chemokines, especially IL-6, TNF-α, and viral infection-related Th1 chemokine CXCL10 through STAT1, STAT3, and MAPK pathways including ERK1/2 and p38, MEK and NF-κB signaling pathways, the over-production of which have been shown to associate with more severe clinical illness during viral infection46. This evidence concerns the gene MAPK3 and viral infectious disease.