Previous studies have showed that corticotropin-releasing factor (CRF) modulates immune response during inflammation. We investigated the effect of CRF family peptides on host resistance to Listeria monocytogenes infection in mice. When mice were administered ip with CRF, urocortin (Ucn), or Ucn2 30 min prior a sublethal infection with L. monocytogenes, the numbers of bacteria in the organs of Ucn2-treated mice were dramatically increased, and most of these mice succumbed. However, host resistance to the infection was retained in CRF- or Ucn-treated mice. The suppressive effect of Ucn2 was dependent on CRF receptor type 2 because an antagonist to the receptor canceled the effect of Ucn2. IL-10 production was significantly increased, and interferon-gamma and TNFalpha production was decreased in the spleens of Ucn2-treated mice, compared with those in Ucn2-untreated control mice. The effect of Ucn2 was canceled by treatment with anti-IL-10 monoclonal antibody and in IL-10-deficient mice. The expression and activation of signal transducers and activators of transcription (STAT) 3 were up-regulated, and the expression and activation of STAT1 were down-regulated in the spleens from Ucn2-treated mice, compared with vehicle-treated mice. Moreover, suppression of TNFalpha production and augmentation of IL-10 production and expression and activation of STAT3 by Ucn2 treatment were observed in heat-killed L. monocytogenes-stimulated macrophages. These results suggested that Ucn2 suppresses host resistance to L. monocytogenes infection via up-regulation of IL-10 production.