Granulocyte–macrophage colony‐stimulating factor regulates cytokine production in cultured macrophages through CD14‐dependent and ‐independent mechanisms

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Abstract
Granulocyte–macrophage colony‐stimulating factor (GM‐CSF) has multiple effects on the antigen phenotype and function of macrophages. In this study we investigated the effect of GM‐CSF on cytokine production by macrophages. We found that GM‐CSF may modify the tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) response to lipopolysaccharide (LPS) through two different mechanisms. Relatively early in culture, GM‐CSF increases the amount of cytokines synthesized by responding cells; this effect appears to be unrelated to modulation of CD14 expression and LPS‐binding capacity. After prolonged incubation, GM‐CSF up‐regulates both CD14 expression and LPS‐binding capacity, and the frequency of cytokine‐producing cells. Release of CD14 in the culture supernatant was decreased in the presence of GM‐CSF, suggesting that a reduced shedding was responsible for the effect of GM‐CSF on CD14 expression. Enhancement of cytokine production was also observed in GM‐CSF‐treated macrophages after stimulation by phorbol 12‐myristate 13‐acetate (PMA), thus indicating that GM‐CSF affects both CD14‐dependent and ‐independent cytokine production. Finally, GM‐CSF did not modulate the LPS‐ and PMA‐induced production of IL‐10 and IL‐12. We conclude that GM‐CSF may play a role in manipulating the activation‐induced expression of pro‐inflammatory cytokines by macrophages. Enhanced production of these cytokines could play an important role in the pathogenesis of Gram‐negative septic shock syndrome and in defence against infectious agents.