Am. J. Respir. Cell Mol. Biol., Volume 21, Number 2, August, 1999 230-237

Stimulation of Neutrophil Interleukin-8 Production by Eosinophil Granule Major Basic Protein

Scott M. Page, Gerald J. Gleich, Kenneth A. Roebuck, and Larry L. Thomas

Department of Immunology/Microbiology, Rush Medical College, Chicago, Illinois; and Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, Minnesota

We evaluated the ability of eosinophil granule major basic protein (MBP) to stimulate interleukin (IL)-8 production by neutrophils. MBP over the concentration range of 0.1 to 10 µM stimulated the release of up to approximately 8 ng/ml IL-8. Incubation with 2 µM MBP showed that, after a 1 h lag, the level of IL-8 release increased with time for approximately 10 h. At the 2 µM concentration, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase did not stimulate significant levels of IL-8 production. MBP stimulated 2-fold increases in IL-8 messenger RNA (mRNA) after 1 and 3 h of incubation, which were blocked by pretreatment with actinomycin D. However, stimulation with MBP did not produce an increase in the binding activity of nuclear factor (NF)-B or activator protein-1. No NF-IL-6 binding activity was detected in the same nuclear extracts. In addition, stimulation with MBP prolonged the stability of IL-8 mRNA. MBP also induced transient increases in mRNA for macrophage inflammatory protein (MIP)-1 and MIP-1, but did not stimulate the release of either chemokine. These findings indicate that MBP is selective among the eosinophil granule proteins as a stimulus for neutrophil IL-8 release and, further, that stimulation of neutrophil IL-8 release by MBP involves both transcriptional and posttranscriptional regulation. We postulate that MBP-induced release of IL-8 by neutrophils may contribute to the pathophysiology of acute asthma and other inflammatory lung diseases.

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