Cytokine-mediated regulation of granulocyte colony-stimulating factor production.

Granulocyte colony-stimulating factor (G-CSF) is an important regulator of granulopoiesis and an inducer of T helper 2 (Th2)-related cytokines. In this study we investigated the mechanism of cytokine-modulated G-CSF production in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) and bone marrow stromal cells (BMSC). In PBMC, LPS significantly induced G-CSF and interleukin (IL)-1, an inducer of G-CSF. Both were partly inhibited by IL-4, IL-6 and IL-10. None of these effects were the result of altered monocyte activation or proliferation. The effects of IL-4 and IL-10 appeared to be independent of IL-1 suppression or IL-1 receptor antagonist (IL-1ra) induction, but rather seemed to involve a blockade of IL-1 function, in addition to a blockade of IL-1-independent stimulatory effects on G-CSF production. The effect of the IL-6-induced suppression of G-CSF production differed from that of IL-4 and IL-10 in that it was much less pronounced and could be partially overridden by addition of functional IL-1, yet it also appeared to involve the interference with IL-1 function and the suppression of IL-1-independent mechanisms. In BMSC, G-CSF synthesis was regulated differently. Here, IL-1 was the main stimulator of G-CSF release, and the effect of IL-1 was neither affected by IL-10 nor IL-6, while IL-4 had a stimulatory effect. Thus, G-CSF production was found to be differently regulated in distinct cellular compartments, and a cross-regulation between these might be facilitated by IL-4-, IL-6- and IL-10-induced inhibition of IL-1. These results could be important for the understanding of G-CSF production in neutropenic patients during severe infection.