HUMAN CYTOMEGALOVIRUS INCREASES CONSTITUTIVE PRODUCTION OF INTERLEUKIN-6 AND LEUKEMIA INHIBITORY FACTOR BY BONE-MARROW STROMAL CELLS

Human cytomegalovirus (CMV) infection is often associated with myelosu ppression and acute inflammatory reaction in immunocompromised patient s. We have previously documented that CMV exposure of bone marrow (BM) stromal cells reduces the capacity of these cells to support hematopo iesis because of a decreased production of colony-stimulating factors. This study examines the potential role of CMV on constitutive and lip opolysaccharide (LPS)-stimulated production of cytokines involved in i nflammatory reaction, interleukin-6 (IL-6) and leukemia inhibitory fac tor (LIF) by BM stromal cells. The release of IL-6 was already detecta ble 2 hours post CMV-infection (2.5-fold increase in production) and t he cumulative production of IL-6 after 5 days of infection was 23 +/- 1.2 ng/mL (ninefold increase in production). CMV was also able to indu ce a time-dependent production of LIF that was maximal 8 hours after C MV infection (2.5-fold increase in production). Concomitantly, there w as no detectable release of granulocyte colony-stimulating factor (G-C SF) and granulocyte-macrophage CSF (GM-CSF) by CMV-infected stromal ce lls. The similar IL-6 and LIF production in the presence of polymyxin B ruled out the possibility that this increase could be caused by cont amination of the viral stock by endotoxin. in addition, ultraviolet-in activated virus behaved similarly to live virus and caused the release of IL-6 and LIF. However, heat-inactivated CMV was unable to induce I L-6 and LIF secretion by BM stromal cells. The production of IL-6 and LIF was also evaluated after stimulation by LPS. After 5 days of CMV e xposure, the LPS-stimulated production of IL-6 and LIF was significant ly lower than uninfected controls, This LPS-induced release of cytokin e production was found to be dependent of viral replication. The exper iments have shown that CMV is a potent inducer of IL-6 and LIF with di fferential effect on constitutive and LPS-stimulated cytokine producti on by stromal cells; we suggest that CMV induction of IL-6 and LIF dur ing the first hours of infection could play a role in CMV-induced infl ammatory reaction, Moreover, our results show that human CMV can distu rb the balanced cytokine network involved in the regulation of hematop oiesis. (C) 1996 by The American Society of Hematology.