Proinflammatory and immunoregulatory functions of interleukin-12

Abstract

Interleukin-12 (IL-12) is a cytokine composed of two chains, a heavy chain or p40, and a light chain or p35, forming a disulfite-linked heterodimer, or p70. IL-12 was originally discovered as a product of human B lymphoblastoid cell lines; however, the most important physiological producers of IL-12 in vitro are phagocytic cells and antigen-presenting cells rather than B cells. The major target cells of IL-12 action are natural killer and T cells, on which IL-12 induce: (1) production of cytokine, particularly interferon-gamma (IFN-gamma); (2) proliferation, in synergy with other mitogenic or costimulatory signals; (3) enhancement of cytotoxic activity. In addition, IL-12 has been described to have stimulatory effects on hematopoietic precursor cells and on B lymphocytes. In vivo, IL-12 is produced very early during infections or immune response, and exerts important proinflammatory functions and enhancement of innate resistance by activating natural killer cells and, through IFN-gamma induction, phagocytic cells. The IL-12 produced during this inflammatory phase, both by direct action and, indirectly, by determining the composition of the cytokine milieu at the site of the murine response, induces differentiation of T helper type 1 (Th1) cells while inhibiting the generation of Th2 cells. Thus, because of its double function of a proinflammatory cytokine and an immunoregulatory factor, IL-12 plays a key role in the resistance to infections, particularly those mediated by bacteria or intracellular parasites, against which phagocytic cell activation and Th1-mediated responses are particularly effective. However, because of the same activities, IL-12 also plays a role in pathological situations, such as septic shock, tissue damage during inflammation and organ-specific autoimmune diseases.