Mammalian homologue of high mobility group box chromatin protein (HMGB) 1 was identified and cloned from human parasites, Schistosoma mansoni and S. haematobium. Sequence analyses showed that the parasite HMGB1s has 35-40% identity to human and rodent HMGB1s, and 33% identity to Caenorhabditis elegans HMGB1. Parasite HMGB1s also contains an A box and B box domain similar to mammalian HMGB1, however, it lacks the C-terminal tail that is present in mammalian HMGB1s. Analysis of the expression of HMGB1 in various life cycle stages of S. mansoni reveal S. mansoni HMGB1 (SmHMGB1) as a stage-specific protein, expressed abundantly in egg and adult female stages and at moderate levels in skin-stage schistosomula. Significant levels of SmHMGB1 were also present in excretory secretions of egg stages. Subsequent characterization studies showed that SmHMGB1 is a potent inducer of pro-inflammatory cytokines such as TNFalpha, IL-1Ralpha, IL-2Ralpha, IL-6, IL-13, IL-13Ralpha1, IL-15 and MIP-1alpha from mouse peritoneal macrophages. Pro-inflammatory activity, especially production of TNFalpha-inducing activity, appears to be a function of the B box domain protein. This was confirmed by both real-time reverse transcription PCR and by cytokine ELISA. Thus, results presented in this study suggest that SmHMGB1 may be a key molecule in the development of host inflammatory immune responses associated with schistosomiasis.