The taming of IL-12: suppressing the production of proinflammatory cytokines.
Interleukin (IL)-12 is a cytokine that possesses both proinflammatory and immunoregulatory activity. IL-12, and the interferon-gamma (IFN-gamma) that is induced by IL-12, play central roles in the development of the Th1-type immune responses that are required for immunity to intracellular pathogens. Recently a number of these pathogens, including Leishmania, measles virus, and human immunodeficiency virus (HIV), have been shown to subvert the development of cell-mediated immunity by actively inhibiting the production of IL-12. Similarly, the ligation of phagocytic receptors on macrophages has also been shown to suppress IL-12 production. The suppression of IL-12 production by receptor ligation occurs by at least two distinct mechanisms: one involves a direct inhibition of gene transcription and the other depends on the production of inhibitory cytokines. We review studies in which IL-12 has been experimentally manipulated, and we compare the mechanisms by which this regulation can occur. Because the IL-12 that is produced during acute inflammation and chronic autoimmune disorders can lead to exacerbated disease, the development of pharmacological means to suppress IL-12 production is currently under investigation. This review focuses on the production of IL-12 by antigen-presenting cells and the methods by which the down-regulation of IL-12 production can be exploited either by pathogens or for therapeutic ends.
Sutterwala
F S
FS
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Mosser
D M
DM
D000818:Animals; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000276:immunology / Q000378:metabolism; D053707:Receptors, Interleukin-12
D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12