The robust production of proinflammatory cytokines and chemokines such as IL-1β, IL-6, IL-8, IL-10, TNF-α, MCP-1, IFN-α, IFN-β, and IFN-γ in mammals during influenza virus infection, referred to as cytokine storms, have been confirmed to contribute to the severity of pathological damage via immune-mediated mechanisms (Walsh et al., 2011; Teijaro et al., 2014). In our study, the expression levels of IL-1β, IL-10, and IFN-β in the lungs and MHC-II in the brain were upregulated to a remarkably high level after infection with ZH283 and SW8, although were greater for ZH283 than SW8. Moreover, the expression level of S1PR1 in tested tissues following infection with ZH283 was less than that following infection with SW8. Consistent with the results of other studies (Walsh et al., 2011; Teijaro et al., 2014), our results demonstrated that the activation of S1PR1 can suppress the induction of cytokines, chemokines, and PRRs, meaning reducing morbidity and mortality, in chickens infected with H5N6. However, the specific mechanism of action remains to be determined.