Regulation of interleukin-8 gene expression after phagocytosis of zymosan by human monocytic cells

Monocyte phagocytosis of pathogens or inflammatory debris leads to chemokin e secretion and heralds the influx of leukocytes to the site of injury. Per sistent chemokine secretion can lead to tissue damage. However, the mechani sms by which phagocytosis regulates chemokine synthesis remain poorly under stood. As a first step, we have studied regulation of interleukin (IL) 8 ge ne expression after interaction with zymosan or latex. IL-8 secretion was c onsistently one- or twofold higher after incubation with zymosan than with latex. Nuclear factor (NF) kappaB translocation to the nucleus was induced by zymosan but not latex, indicating that its translocation is dependent on the nature of the phagocytic stimulus. NF kappaB activation coincided with I kappaB alpha degradation but had no effect on processing of NF kappa B1/ p105, the precursor of the NF kappaB protein p50. The NF kappaB inhibitor g liotoxin abrogated zymosan-induced IL-8 synthesis in peripheral blood monoc ytes, further demonstrating that the induction of IL-8 mRNA by zymosan is N F kappaB dependent. SB203580 inhibition of the p38 mitogen-activated protei n kinase (MAPK) pathway significantly decreased zymosan-induced IL-8 mRNA a ccumulation. Inhibitors of protein kinases A and C or tyrosine kinases had no significant effect on zymosan-induced IL-8 synthesis. These data indicat e that p38 MAPK and NF kappaB are critical in controlling zymosan-induced I L-8 secretion.