Interleukin 10 (IL-10) inhibits human lymphocyte interferon γ-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells

Abstract

Natural killer cell stimulatory factor or interleukin 12 (NKSF/IL-12) is a heterodimeric cytokine produced by monocytes/macrophages, B cells, and possibly other accessory cell types primarily in response to bacteria or bacterial products. NKSF/IL-12 mediates pleiomorphic biological activity on T and NK cells and, alone or in synergy with other inducers, is a powerful stimulator of interferon γ (IFN-γ) production. IL-10 is a potent inhibitor of monocyte-macrophage activation, that inhibits production of tumor necrosis factor α (TNF-α), IL-1 and also IFN-γ from lymphocytes acting at the level of accessory cells. Because TNF-α and IL-1 are not efficient inducers of IFN-γ, the mechanism by which IL-10 inhibits IFN-γ production is not clear. In this paper, we show that IL-10 is a potent inhibitor of NKSF/IL-12 production from human peripheral blood mononuclear cells activated with Staphylococcus aureus or lipopolysaccharide (LPS). Both the production of the free NKSF/IL-12 p40 chain and the biologically active p70 heterodimer are blocked by IL-10. NKSF/IL-12 p40 chain mRNA accumulation is strongly induced by S. aureus or LPS and downregulated by IL-10, whereas the p35 mRNA is constitutively expressed and only minimally regulated by S. aureus, LPS, or IL-10. Although IL-10 is able to block the production of NKSF/IL-12, a powerful inducer of IFN-γ both in vitro and in vivo, the mechanism of inhibition of IFN-γ by IL-10 cannot be explained only on the basis of inhibition of NKSF/IL-12 because IL-10 can partially inhibit IFN-γ production induced by NKSF/IL-12, and also, the IFN-γ production in response to various stimuli in the presence of neutralizing antibodies to NKSF/IL-12. Our findings that antibodies against NKSF/IL-12, TNF-α, or IL-1β can significantly inhibit IFN-γ production in response to various stimuli and that NKSF/IL-12 and IL-1β can overcome the IL-10-mediated inhibition of IFN-γ, suggest that IL-10 inhibition of IFN-γ production is primarily due to its blocking production from accessory cells of the IFN-γ-inducer NKSF/IL-12, as well as the costimulating molecule IL-1β.