Abstract: Disclosed is the surprising discovery that a single amino acid provides the demarcation between the immunosuppressive and immunostimulatory properties of the cytokine, IL-10. The present invention thus provides mammalian and human IL-10 genes and polypeptides that have immunosuppressive properties, without immunostimulatory side-effects. Also provided are various methods of using the new IL-10 constructs, both in vitro and in vivo, particularly in sole or combination therapies involving immunosuppression, such as in the treatment of inflammatory diseases and disorders, and in transplantation.