Human neutrophils produce interferon gamma upon stimulation by interleukin-12

Interferon gamma (IFNgamma) is a Th1 cytokine mainly produced by T cells, NK cells and macrophages in response to interleukin (IL)-12. As polymorphonuclear neutrophils (PMN) have been shown to produce and to release numerous cytokines, in particular upon IL-12 stimulation, we investigated the ability of highly purified PMN to secrete IFNgamma. We found that PMN contained a small store of IFNgamma, and that this store was rapidly secreted upon stimulation by degranulating agents such as formyl peptides. Moreover, after a few hours of stimulation with appropriate agents, PMN synthesized IFNgamma. The effect of IL-12 was time- and concentration-dependent, and IL-12 combinations with IL-2, IL-15, IL-18 or LIPS were highly synergistic. Cycloheximide inhibited IFNgamma release in such optimal conditions, confirming the ability of PMN to synthesize IFNgamma. IFNgamma synthesis was associated with an increase in specific mRNA content, pointing to a transcriptional mechanism. The IFNgamma produced by PMN was biologically active, as demonstrated by its ability to induce TNFalpha synthesis by PMN themselves or to induce IL-10 synthesis by peripheral blood mononuclear cells. These findings reveal a novel pathway of autocrine and paracrine PMN activation. They also identified a new role for IFNgamma, bridging innate and adaptive immune responses.