OBJECTIVES: To investigate the effect of forskolin, on susceptibility/severity of acute pyelonephritis and innate immune responses to pathogen using an established experimental model of ascending urinary tract infection and primary cell cultures (i.e. renal tubular epithelial cells, monocytes/macrophages). METHODS: Forskolin is produced by the Indian Coleus plant (Coleus forskohlii), which is commonly used to raise levels of cyclic AMP (cAMP) in the study and research of cell physiology. Forkolin (250mg/kg) was given before the induction of infection by i.p. injection. Kidney infection was assessed in forskolin or control reagent treated mice at 6, 24, 48h after bladder inoculation of UPEC (J96). Bacteria load in kidneys was analyzed by the agar plate assay. Tissue damage was assessed by histopathology. Leukocytes infiltration was analysed by immunochemical staining, tissue MPO activity assay and flow cytometry. Renal synthesis of cytokines/chemokines was analysed by RT-PCR. RESULTS: Administration of forskolin significantly reduced bacteria load in kidneys and renal tissue damage at both 6 and 24h time points by 10 folds, this was associated with reduced intrarenal production of pro-inflammatory cytokines and chemokines (e.g. TNF-α, IL-1β, KC, MCP-1) and attenuated intrarenal infiltration and accumulation of leukocytes (i.e. CD45+. Gr-1+, F4/80+) as well as intrarenal myeloperoxidase (MPO) activity. In vitro, forskolinI inhibited LPS or UPEC mediated pro-inflammatory cytokine and chemokine production by primary renal tubular epithelial cells and monocytes/macrophages. CONCLUSIONS:  These findings demonstrate that administration of forskolin is beneficial for controlling the development of UPEC mediated acute pyelonephritis in mice. The protective effect of forskolin (via cAMP activation) in this experimental acute pyelonephritis can be explained at least in part by limiting excessive inflammatory responses through acting on both renal parenchymal and inflammatory cells.