Natural killer cell stimulatory factor (NKSF) or interleukin-12 is a key regulator of immune response and inflammation

Abstract

Natural Killer cell Stimulatory Factor (NKSF) or interleukin-12 (IL-12) is a heterodimeric cytokine of 70 kDa formed by a heavy chain of 40 kDa (p40) and a light chain of 35 kDa (p35). Although it was originally identified and purified from the supernatant of Epstein-Barr virus-transformed B cell lines, it has been shown that among peripheral blood cells $\text{NKSF}\text{IL-12}$ is predominantly produced by monocytes, with lower production by B cells and other accessory cells. The most powerful inducers of $\text{NKSF}\text{IL-12}$ production are bacteria, bacterial products and parasites. In addition to the biologically active p70 heterodimer, the cells producing $\text{NKSF}\text{IL-12}$ also secrete a large excess of monomeric p40, a molecule with no demonstrable biological activity. $\text{NKSF}\text{IL-12}$ is active on T lymphocytes and NK cells on which it induces production of lymphokines, enhancement of cytotoxic activity and mitogenic effects. $\text{NKSF}\text{IL-12}$ induces T and NK cells to produce IFN-γ and synergizes with other IFN-γ inducers in this effect. In vitro, and probably in vivo, $\text{NKSF}\text{IL-12}$ is required for optimal IFN-γ production. When human lymphocytes are stimulated with antigens in vitro, addition of exogenous $\text{NKSF}\text{IL-12}$ to the culture induces differentiation of T helper type 1 (Th1) cells, whereas neutralization of endogenous $\text{NKSF}\text{IL-12}$ with antibodies favors differentiation of Th2 cells. IFN-γ, a product of Th1 cells, enhances $\text{NKSF}\text{IL-12}$ production by mononuclear cells, whereas IL-10 and IL-4, products of Th2 cells, efficiently inhibit it. Therefore, $\text{NKSF}\text{IL-12}$ appears to be an important inducer of Th1 responses produced by accessory cells during early antigenic stimulation and its production is regulated by a positive feedback mechanism mediated by Th1 cells through IFN-γ and a negative one by Th2 cells through IL-10 and IL-4. The balance of IL-12 production versus IL-10 and IL-4 production early during an immune response might therefore be instrumental in determining Th1-type versus Th2-type immune responses. Because of this potential role of IL-12 during immune responses, our results demonstrating the impaired ability of HIV seropositive patients to produce $\text{NKSF}\text{IL-12}$ in response to bacterial stimulation suggest that this defect in $\text{NKSF}\text{IL-12}$ production might be a factor contributing to their immune depression.