Cytotoxic factors released by dengue virus-infected human blood monocytes

Human monocyte-derived cytotoxic factors (CF) induced by dengue virus were studied. Using several human leukemia cell lines as precursors, the biological activities of CF in conditioned medium from dengue virus-infected monocytes were demonstrated through the measurement of tumor cell growth inhibition. The conditioned medium from dengue virus infected monocytes suppressed significantly growth of CEM, HL60, K562, and U937 cells. In the presence of 10% conditioned medium (v/v) from dengue virus infected monocytes, DNA synthesis of U937 cells, as measured by [3H]thymidine incorporation, decreased by 99% in contrast to their synthesis in conditioned medium from noninfected control monocytes, which did not have any suppressive effect. Partial characterization of CF showed that it is a proteinase-K-sensitive and heat-labile protein with a molecular mass over 100 kDa. Employing a flow cytometric analysis of the cell cycle, it was found that U937 cells, treated either with conditioned medium from dengue virus infected monocytes or with CF, but not treated with conditioned medium from noninfected monocytes, showed cell-cycle arrest in G1 phase by 48 hr. This suppressive effect of CF on U937 growth was dose- and time-dependent. These results suggest that dengue virus-infected monocytes may produce CF to target myeloid cells, resulting in the hematological changes observed in patients with dengue fever.