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Monocyte phagocytosis of pathogens or inflammatory debris leads to chemokine secretion and heralds the influx of leukocytes to the site of injury. Persistent chemokine secretion can lead to tissue damage. However, the mechanisms by which phagocytosis regulates chemokine synthesis remain poorly understood. As a first step, we have studied regulation of interleukin (IL) 8 gene expression after interaction with zymosan or latex. IL-8 secretion was consistently one- or twofold higher after incubation with zymosan than with latex. Nuclear factor (NF) κB translocation to the nucleus was induced by zymosan but not latex, indicating that its translocation is dependent on the nature of the phagocytic stimulus. NFκB activation coincided with IκBα degradation but had no effect on processing of NFκB1/p105, the precursor of the NFκB protein p50. The NFκB inhibitor gliotoxin abrogated zymosan-induced IL-8 synthesis in peripheral blood monocytes, further demonstrating that the induction of IL-8 mRNA by zymosan is NFκB dependent. SB203580 inhibition of the p38 mitogen-activated protein kinase (MAPK) pathway significantly decreased zymosan-induced IL-8 mRNA accumulation. Inhibitors of protein kinases A and C or tyrosine kinases had no significant effect on zymosan-induced IL-8 synthesis. These data indicate that p38 MAPK and NFκB are critical in controlling zymosan-induced IL-8 secretion.