Regulation of neutrophil-derived IL-8: The role of prostaglandin E2, dexamethasone, and IL-4

William A. Wertheim, Steven L. Kunkel, Theodore J. Standiford, Marie D. Burdick, Frank S. Becker, Carol A. Wilke, Andrew R. Gilbert, Robert M. Strieter

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118 Scopus citations

Abstract

Historically, the neutrophil has been perceived as a terminally differentiated leukocyte with limited ability to produce de novo proteins. Furthermore, in the context of acute inflammation the activated neutrophil has been appreciated only for its ability to release various proteases, reactive oxygen, and arachidonic acid metabolites. Recently, the neutrophil has been shown to have the capacity to produce a number of cytokines that may be instrumental in orchestrating the progression of acute inflammation to a more chronic and specific immune response. These cytokines include IFN-α, M- CSF, G-CSF, TNF, IL-1, and IL-6. Our laboratory and others have shown the neutrophils produce IL-8 in response to LPS or a phagocytic challenge. Although these studies have shown the induction of IL-8 from polymorphonuclear neutrophils (PMN), relatively little is known regarding the regulation of PMN-derived IL-8. Because PMN and monocytes share the same stem cell, and monocyte-derived IL-8 is regulated by prostaglandin E2 (PGE2), glucocorticoids (dexamethasone; DEX), and the T-Lymphocyte-derived IL-4, we postulated that PMN-derived IL-8 production may be regulated in a similar manner. To test this hypothesis, PMN were isolated (> 99% pure) from peripheral blood and cultured in media with 5% FCS in the presence or absence of LPS (10 ng/ml; a concentration of LPS that induced the half-maximal production of PMN-derived IL-8) and in the presence or absence of DEX (10- 6 M to 10-10 M), PGE2 (10-6 M to 10-10 M), or IL-4 (100 ng/ml to 100 pg/ml). PMN-derived IL-8 was measured using a specific sandwich ELISA. DEX and IL-4 in the presence of LPS were found to inhibit PMN-derived IL-8 in both a dose- and time-dependent fashion. DEX and IL-4 in concentrations of 10-6 M and 10 ng/ml resulted in maximal inhibition of LPS-induced PMN- derived IL-8, respectively. Moreover, both DEX and IL-4 administration could be delayed 4 hr post-stimulation with LPS and result in significant suppression of PMN-derived IL-8. Interestingly, in contrast to the regulation of monocyte-derived IL-8 by PGE2, PGE2 treatment of PMN failed to inhibit the generation of LPS-induced IL-8. Northern blot analysis of steady-state IL-8 mRNA demonstrated that both DEX and IL-4 treatment of PMN resulted in a 40 and 52% reduction in LPS-stimulated PMN-derived IL-8 mRNA, respectively. These results support the notion that the PMN is an active and dynamic participant of an inflammatory/immune response through the production of IL- 8, and that this generation is susceptible to regulation by the immunomodulating agents, DEX and IL-4.

Original languageEnglish (US)
Pages (from-to)2166-2175
Number of pages10
JournalJournal of Immunology
Volume151
Issue number4
StatePublished - Jan 1 1993

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Wertheim, W. A., Kunkel, S. L., Standiford, T. J., Burdick, M. D., Becker, F. S., Wilke, C. A., Gilbert, A. R., & Strieter, R. M. (1993). Regulation of neutrophil-derived IL-8: The role of prostaglandin E2, dexamethasone, and IL-4. Journal of Immunology, 151(4), 2166-2175.