Interleukin (IL)-1 and IL-4 synergistically stimulate NF-IL6 activity and IL-6 production in human mesangial cells

Background. While interleukin (IL)-4 inhibits pro-inflammatory cytokine expression by human monocytes, we have observed that it potentiates IL-6 production by IL-1-activated human mesangial cells (MC). To study the mechanism of this cell-type specific interaction between IL-1 and IL-4 in MC, we examined the effect of both cytokines on the activities of nuclear factor κB (NF-κB) and nuclear factor IL-6 (NF-IL6), transcription factors that are essential for IL-6 gene expression. Methods. We evaluated IL-6 synthesis, mRNA expression, and mRNA stability by ELISA, Northern analysis, and the actinomycin D method, respectively. Activities of NF-κB and NF-IL6 were analyzed by gel shift assay. Results. IL-4 augmented the IL-1 stimulated IL- 6 mRNA levels by about threefold without altering mRNA stability. IL-1 treatment rapidly induced the binding activity of NF-κB. In contrast, IL-4 did not affect basal and IL-1-induced NF-κB activities. Both IL-1 and IL-4 stimulated NF-IL6 activity as early as 30 minutes after treatment. When MC were treated with both cytokines together, marked activation of NF-IL6 was observed at five hours. Conclusions. These results suggest that simultaneous activation of NF-κB and NF-IL6 is essential for IL-6 gene expression and that IL-1 and IL-4 cooperatively stimulate MC IL-6 production through their synergistic activation of NF-IL6.