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Staphylococcus aureus causes the majority of human skin and soft tissue infections, and is a major infectious cause of mortality. However, host defense mechanisms against S. aureus are incompletely understood. Interleukin (IL)-19, -20, and -24 signal through STAT3-dependent type I and type II IL-20 receptors and have been associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We hypothesized these cytokines may play a role in S. aureus skin infections. We show here that this family of cytokines promotes cutaneous S. aureus infection in mice by STAT3-dependent mechanisms that down-regulate IL-1 beta- and IL-17A-dependent inflammatory pathways required for control of infection. Inhibition of IL-1 beta by these cytokines was consistent with their demonstrated rapid inactivating sumoylation of C/EBP beta, a transcriptional activator of IL-1 beta. Similar effects of these cytokines were seen in human keratinocytes after S. aureus exposure, and antibody blockade of IL-20 receptor signaling improved infectious outcomes in mice. Our findings identify an immunosuppressive role for these cytokines during infection that may be therapeutically targeted to alter infectious susceptibility. [ABSTRACT FROM AUTHOR]