REGULATORY EFFECTS OF T-CELL LYMPHOKINES ON CYTOKINE GENE-EXPRESSION IN MONOCYTES

Hematopoiesis is regulated by colony-stimulating factors (CSF) and man y other cytokines. T helper cell and monocyte/macrophage interactions that take place in the immune response, resulting in the production of many cytokines, probably can influence inducible hematopoiesis. We in vestigated the effect of the T helper cell-derived lymphokines IL-2, I L-3, GM-CSF, and IFN-gamma, on the expression of cytokine genes in mon ocytes and compared this to LPS-induced cytokine gene expression in mo nocytes. To avoid inadvertent activation of monocytes, cells were puri fied by elutriation and cultured under serum-free, LPS-free, and nonad herent conditions. Similar to LPS, IL-2, IL-3, and GM-CSF induced the expression of IL-1beta, IL-6, IL-8, TNF-alpha, and IL-1-RA genes in mo nocytes, but with some differences in the amount and kinetics of cytok ine mRNA accumulation. Unlike LPS, IL-2, IL-3, and GM-CSF did not indu ce G-CSF and GM-CSF gene expression in monocytes. GM-CSF and IL-3 were the only inducers capable of expressing the M-CSF gene in monocytes. IL-2, IL-3, and GM-CSF showed no effect on the IL-10 gene while IFN-ga mma appeared to have no effect on any of the cytokine genes studied in monocytes. These data indicate that in the immune response expression of the proinflammatory cytokine genes, IL-1beta, IL-6, IL-8, and TNF- alpha, can occur and that autoregulatory control mechanisms, like the expression of IL-1-RA gene, are also activated. It is not likely that the immune response has a direct effect on inducible granulopoiesis, b ecause no induction of G-CSF or GM-CSF was found in monocytes stimulat ed with T helper lymphokines. The induction of G-CSF and, to a lesser extent, GM-CSF gene expression in monocytes by the microbial product L PS suggests that the pathogen itself is of greater importance in regul ating granulopoiesis.