During the early aspecific phase of host defense, production of interferon (IFN)-gamma by natural killer cells plays an important role in bringing about acute inflammation, mainly because of the activating effects of IFN-gamma on adhesive properties of endothelial cells and on mediator production by mononuclear phagocytes (MPCs). In the subsequent antigen-specific phase of the immune response, IFN-gamma acts as a regulator of antigen presentation and of proliferation and differentiation of lymphocyte populations. Immunosuppressive as well as immunostimulatory effects may result from these actions. High-level production of IFN-gamma during this phase of host defense is now classically seen as a hallmark of a T-helper 1 (TH1)-type reaction, characterized by activation of antimicrobial activity of macrophages and by inflammatory reactions with a DTH character. Development of TH1-type lymphocyte populations producing IFN-gamma is regulated by other cytokines including interleukin (IL)-12. In many systems IL-12 and IFN-gamma act in a similar fashion, and a current subject of debate is the question of whether all activities of IL-12 are mediated by IFN-gamma. Another question is whether IFN-gamma, by its ability to potentiate MPCs' ability to produce IL-12, plays a role in bringing about or stabilizing TH1 type responses. In two model systems of autoimmune disease, experimental autoimmune encephalomyelitis and collagen-induced arthritis, IL-12 and IFN-gamma were found to act independently.