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(Journal of Leukocyte Biology. 2001;70:447-454.)
© 2001 by Society for Leukocyte Biology

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

Jon S. Friedland*, Despina Constantin{dagger}, Terry C. Shaw* and Eleni Stylianou{dagger}

* Department of Infectious Diseases, Imperial College of Science, Technology and Medicine (Hammersmith Campus), London, and
{dagger} School of Biomedical Sciences and Institute of Cell Signalling, University Hospital, Nottingham, United Kingdom

Correspondence: Dr. Eleni Stylianou, School of Biomedical Sciences, University Hospital, Nottingham, United Kingdom. E-mail: eleni.stylianou{at}nottingham.ac.uk

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) {kappa}B 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{kappa}B activation coincided with I{kappa}B{alpha} degradation but had no effect on processing of NF{kappa}B1/p105, the precursor of the NF{kappa}B protein p50. The NF{kappa}B inhibitor gliotoxin abrogated zymosan-induced IL-8 synthesis in peripheral blood monocytes, further demonstrating that the induction of IL-8 mRNA by zymosan is NF{kappa}B 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 NF{kappa}B are critical in controlling zymosan-induced IL-8 secretion.

Key Words: chemokine synthesis • MAPK • tyrosine kinase • protein kinase • NF-{kappa}B activation




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