title: Regulation of neutrophil-derived IL-8: the role of prostaglandin E2, dexamethasone, and IL-4.
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-alpha, M-CSF, G-CSF, TNF, IL-1, and IL-6. Our laboratory and others have shown that 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.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor 48109-0360.
authors.forename: W A
authors.initials: WA
authors.lastname: Wertheim
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: T J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: M D
authors.initials: MD
authors.lastname: Burdick
authors.forename: F S
authors.initials: FS
authors.lastname: Becker
authors.forename: C A
authors.initials: CA
authors.lastname: Wilke
authors.forename: A R
authors.initials: AR
authors.lastname: Gilbert
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
mesh_terms: D001483:Base Sequence; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000502:physiology*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D016209:Interleukin-8; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D015847:Interleukin-4; D003907:Dexamethasone; D015232:Dinoprostone