Interferon-γ Produced by EBV-Positive Neoplastic NK-Cells Induces Differentiation into Macrophages and Procoagulant Activity of Monocytes, Which Leads to HLH

SIMPLE SUMMARY: Epstein–Barr virus (EBV), a common virus all over the world, infects not only B-cells but also T- and NK-cells. Once infected with EBV, human beings remain infected for life, and EBV renders infected B-cells immortal. EBV-positive NK-cell neoplasms, such as extranodal NK/T-cell lymphoma of nasal type, aggressive NK-cell leukemia, and chronic active EBV infection, are relatively rare but lethal disorders. They show systemic inflammation and progress to hemophagocytic lymphohistiocytosis (HLH), a life-threatening state of immune hyperactivation. The suppression and prevention of HLH are important to treat the neoplasms. Revealing the mechanism will pave a new path for treatment. We show herein that IFN-γ produced by EBV-positive neoplastic NK-cell is responsible for inducing the differentiation and the activation of M1-like macrophages. Suppressing IFN-γ may regulate HLH in EBV-positive NK-cell neoplasms. ABSTRACT: Epstein–Barr virus (EBV)-positive T- or NK-cell neoplasms show progressive systemic inflammation and abnormal blood coagulation causing hemophagocytic lymphohistiocytosis (HLH). It was reported that inflammatory cytokines were produced and secreted by EBV-positive neoplastic T- or NK-cells. These cytokines can induce the differentiation of monocytes into macrophages leading to HLH. To clarify which products of EBV-positive neoplastic T- or NK-cells have effects on monocytes, we performed a co-culture assay of monocytes with the supernatants of EBV-positive T- or NK-cell lines. The expression of differentiation markers, the phagocytosis ability, and the mRNA expression of the inflammatory cytokines of THP-1, a monocytic cell line, clearly increased after culturing with the supernatants from EBV-NK-cell lines. Co-culturing with the supernatants promoted the expression of CD80 and CD206 as well as M1 and M2 macrophage markers in human monocytes. Co-culturing with the supernatants of EBV-NK-cell lines significantly enhanced the procoagulant activity and the tissue factor expression of monocytes. Interferon (IFN)-γ was elevated extremely not only in the supernatant of EBV-NK-cell lines but also in the plasma of EBV-positive NK-cell neoplasms patients accompanying HLH. Finally, we confirmed that IFN-γ directly enhanced the differentiation into M1-like macrophages and the procoagulant activity of monocytes. Our findings suggest that IFN-γ may potentially serve as a therapeutic target to regulate HLH in EBV-positive NK-cell neoplasms.