EFFECTS OF IL-3 AND LPS ON TRANSCRIPTION FACTORS INVOLVED IN THE REGULATION OF IL-6 MESSENGER-RNA

Recently it has been demonstrated that in vivo application of interleu kin-3 (IL-3) is associated with the release of IL-6. This observation suggests that the transcription factors triggered by IL-3 are in great homology with the transcription factors induced by lipopolysaccharide (LPS). The results of the present study with in vitro activated human monocytes demonstrate that IL-3 alone is incapable of inducing IL-6 m RNA, but primes monocytes to enhance the IL-6 mRNA expression when co- stimulated with LPS. The difference in effect between IL-3 and LPS mig ht be related to our observation that IL-3 induces the p50 subunit of the transcription factor nuclear factor-kappa B (NF-kappa B), whereas LPS appears to induce both the p50 as well as the p65 subunit of NF-ka ppa B, as demonstrated with RNA studies and electrophoretic mobility s hift assays (EMSA). However, no difference was found with regard to th e induction of activator protein-1 (AP-1) and NF-IL6 after treatment w ith IL-3 or LPS alone. Priming with IL-3 followed by LPS stimulation i s associated with a reduced expression of NF-kappa B without changing the composition of the complex. In addition, a reduced expression of c -fos and c-jun mRNA was noticed, combined with a reduced DNA binding a ctivity of AP-1. However, the expression of NF-IL6 was enhanced when p riming with IL-3 followed by LPS. Since AP-1 has been suggested as neg ative regulator of the IL-6 gene expression, it is conceivable that, a fter priming with IL-3, the reduced DNA binding activity of AP-1, in c onjunction with the increased DNA binding of NF-IL6, might result in a synergistic effect on IL-6 mRNA expression, when compared to stimulat ion with LPS alone.