The effects of glucocorticoids on human eosinophils
Authors: Robert P. Schleimer, Bruce S. Bochner
Journal: Journal of Allergy and Clinical Immunology (1994)

The purpose of this brief review is to give an overview of the current literature on the influence of glucocorticoids (steroids) on human eosinophils. This cell type is believed to be critically involved in both chronic allergic diseases and experimental allergic reactions.1Sur S Adolphson CR Gleich GJ Eosinophils: biochemical and cellular aspects.in: 4th ed. Allergy: principles and practice. : Mosby, St. Louis1993: 169-200Google Scholar, 2Bousquet J Chuez P LaCoste JY et al.Eosinophilic inflammation in asthma.N Engl J Med. 1991; 324: 1033-1039Google Scholar Eosinophils are now suspected to be responsible for many of the pathologic features of asthma; toxic eosinophil granule proteins such as major basic protein and eosinophil-derived leukotrienes have been implicated in airway reactivity, vascular leak syndromes, destruction and sloughing of epithelium, and other inflammatory changes that are pathognomonic of asthma.3Flavahan NA Slifman NR Gleich GJ Vanhoutte PM Human eosinophil major basic protein causes hyperreactivity of respiratory smooth muscle.Am Rev Respir Dis. 1988; 138: 685-688Crossref PubMed Scopus (177) Google Scholar, 4Gundel RH Letts LG Gleich GJ Human eosinophil major basic protein induces airway constriction and airway hyperresponsiveness in primates.J Clin Invest. 1991; 87: 1470-1473Crossref PubMed Scopus (269) Google Scholar It is clear that eosinophils contain the glucocorticoid receptor and are important targets of glucocorticoid action.5Prin L Lefebvre PP Gruart V et al.Heterogeneity of human eosinophil glucocorticoid receptor expression in hypereosinophilic patients: absence of detectable receptor correlates with resistance to corticotherapy.Clin Exp Immunol. 1989; 78: 383-389PubMed Google Scholar, 6Schleimer RP Glucocorticosteroids: their mechanism of action and use in allergic diseases.in: 4th ed. Allergy: principles and practice. : Mosby, St. Louis1993: 893-925Google Scholar Emphasis is placed on the effects of glucocorticoids on production, function, and survival of human eosinophils. In vitro studies are considered first, then in vivo findings; as appropriate, studies in animals are also discussed. Numerous studies have established that the formation of eosinophil-rich colonies in bone marrow colony assays is inhibited by the presence of steroids in the culture system.7Bjornson BH Harvey JM Rose L Differential effect of hydrocortisone on eosinophil and neutrophil proliferation.J Clin Invest. 1985; 76: 924-929Crossref PubMed Scopus (51) Google Scholar, 8Slovick FT Abboud CN Brennan JK Lichtman MA Modulation of in vitro eosinophil progenitors by hydrocortisone: role of accessory cells and interleukins.Blood. 1985; 66: 1072-1079PubMed Google Scholar, 9Butterfield JH Ackerman SJ Weiler D Eisenbrey AB Gleich GJ Effects of glucocorticoids on eosinophil colony growth.J ALLERGY CLIN IMMUNOL. 1986; 78: 450-457Abstract Full Text PDF PubMed Scopus (21) Google Scholar Interpretation of the reported findings is difficult because of the intrinsic nature of colony-forming assays, which often involve several cell types in addition to the relevant progenitor cells. Bjornson et al.7Bjornson BH Harvey JM Rose L Differential effect of hydrocortisone on eosinophil and neutrophil proliferation.J Clin Invest. 1985; 76: 924-929Crossref PubMed Scopus (51) Google Scholar showed that steroids reduced eosinophilic colonies generated from bone marrow or peripheral blood when a conditioned medium derived from activated peripheral blood mononuclear cells was used as the source of the growth factor. If steroid was added during preparation of the conditioned medium, a large decrease in colony-stimulating activity was also observed.7Bjornson BH Harvey JM Rose L Differential effect of hydrocortisone on eosinophil and neutrophil proliferation.J Clin Invest. 1985; 76: 924-929Crossref PubMed Scopus (51) Google Scholar Slovich et al.8Slovick FT Abboud CN Brennan JK Lichtman MA Modulation of in vitro eosinophil progenitors by hydrocortisone: role of accessory cells and interleukins.Blood. 1985; 66: 1072-1079PubMed Google Scholar likewise demonstrated that steroids inhibit eosinophil colony formation induced by exogenously added growth factor. Interestingly, when the growth factor was derived from either activated peripheral blood mononuclear cells or the MO cell line, the inhibitory effect was much less than when supernatants from a macrophage-like cell line (GCT) were used, possibly because the former contain more "eosinophil–colony stimulating factor" (interleukin [IL]-5 or granulocyte-macrophage colony-stimulating factor [GM-CSF?]) than the latter. These authors also showed that steroids inhibit "eosinophil–colony stimulating factor" production by monocytes and that the steroid had no effect on colony formation when purified progenitors were used (at that time, mononuclear and T cell-depleted bone marrow). Slovick et al.8Slovick FT Abboud CN Brennan JK Lichtman MA Modulation of in vitro eosinophil progenitors by hydrocortisone: role of accessory cells and interleukins.Blood. 1985; 66: 1072-1079PubMed Google Scholar concluded that steroids inhibit eosinophil colony formation indirectly by diminishing the release of cytokines (IL-1, IL-2) by cells in the colony assay. Recent studies by Shalit et al.10Shalit M Sekhsaria S Malech HL Modulation of growth and differentiation of eosinophils from human peripheral blood CD34 + cells by IL5 and other growth factors.J ALLERGY CLIN IMMUNOL. 1994; 93 ([Abstract]): 268Google Scholar have shown that the formation of eosinophil colonies by stimulation of purified CD34+ primitive hematopoietic progenitor cells with purified cytokines (IL-5, IL-3, GM-CSF) is not inhibited by steroids, supporting the concept that steroid effects on eosinophil colony formation result indirectly from inhibition of the release of factors that induce eosinophil colony growth. Because IL-5 has been shown to be the primary eosinophilopoietic cytokine and because IL-5 production is inhibited by steroids, the most direct hypothesis to explain the above-described results is that steroid inhibition of IL-5 production by bone marrow cells is responsible for the suppression of colony growth.11Sanderson CJ Warren DJ Strath M Identification of a lymphokine that stimulates eosinophil differentiation in vitro.J Exp Med. 1985; 162: 60-74Crossref PubMed Scopus (225) Google Scholar, 12Yamaguchi Y Suda T Suda J et al.Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors.J Exp Med. 1988; 167: 43-56Crossref PubMed Scopus (464) Google Scholar, 13Sher A Coffman RL Hieny S Cheever AW Ablation of eosinophil and IgE responses with anti-IL-5 or anti-IL-4 antibodies fails to affect immunity against Schistosoma mansoni in the mouse.J Immunol. 1990; 145: 3911-3916PubMed Google Scholar, 14Rolfe FG Hughes JM Armour CL Sewell WA Inhibition of interleukin-5 gene expression by dexamethasone.Immunology. 1992; 77: 494-499PubMed Google Scholar Leukocyte adhesion can be induced by stimulation of leukocytes, stimulation of endothelium, or both.15Butcher EC Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity.Cell. 1991; 67: 1033-1036Abstract Full Text PDF PubMed Scopus (2515) Google Scholar, 16Harlan J Liu D Adhesion: its role in inflammatory disease.in: : WH Freeman and Company, New York1992: 1-202Google Scholar, 17Springer TA Adhesion receptors of the immune system.Nature. 1990; 346: 425-434Crossref PubMed Scopus (5845) Google Scholar, 18Bochner BS Schleimer RP The role of adhesion molecules in human eosinophil and basophil recruitment.J ALLERGY CLIN IMMUNOL. 1994; 94: 427-438Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar Both processes appear to be involved in vivo in allergic reactions. In vitro, endothelial expression of adhesion molecules can be activated by the cytokines IL-1 and tumor necrosis factor (TNF). These cytokines induce expression of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular cell adhesion molecule-1 (VCAM-1), all of which can bind to their respective counterligands on the surface of leukocytes, including eosinophils.18Bochner BS Schleimer RP The role of adhesion molecules in human eosinophil and basophil recruitment.J ALLERGY CLIN IMMUNOL. 1994; 94: 427-438Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 19Albelda SM Buck CA Integrins and other cell adhesion molecules.FASEB J. 1990; 4: 2868-2880Crossref PubMed Scopus (1631) Google Scholar IL-4 and IL-13 can induce endothelial cells to express VCAM-1 and not the other adhesion molecules20Thornhill MH Kyan-Aung U Haskard DO IL-4 increases human endothelial cell adhesiveness for T cells but not for neutrophils.J Immunol. 1990; 144: 3060-3065PubMed Google Scholar, 21Schleimer RP Sterbinsky SA Kaiser J et al.Interleukin-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium: association with expression of VCAM-1.J Immunol. 1992; 148: 1086-1092PubMed Google Scholar (and unpublished observations). VCAM-1 binds to VLA-4 on the surface of eosinophils and causes adhesion.21Schleimer RP Sterbinsky SA Kaiser J et al.Interleukin-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium: association with expression of VCAM-1.J Immunol. 1992; 148: 1086-1092PubMed Google Scholar, 22Bochner BS Luscinskas FW Gimbrone Jr, MA et al.Adhesion of human basophils, eosinophils, and neutrophils to IL-1-activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules.J Exp Med. 1991; 173: 1553-1557Crossref PubMed Scopus (583) Google Scholar, 23Dobrina A Menegazzi R Carlos TM et al.Mechanisms of eosinophil adherence to cultured vascular endothelial cells: eosinophils bind to the cytokine-induced endothelial ligand vascular cell adhesion molecule-1 via the very late activation antigen-4 integrin receptor.J Clin Invest. 1991; 88: 20-26Crossref PubMed Scopus (251) Google Scholar, 24Walsh GM Mermod J Hartnell A Kay AB Wardlaw AJ Human eosinophil, but not neutrophil, adherence to IL-1-stimulated human umbilical vascular endothelial cells is α4β1 (very late antigen-4) dependent.J Immunol. 1991; 146: 3419-3423PubMed Google Scholar, 25Weller PF Rand TH Goelz SE Chi-Rosso G Lobb RR Human eosinophil adherence to vascular endothelium mediated by binding to vascular cell adhesion molecule 1 and endothelial leukocyte adhesion molecule 1.Proc Natl Acad Sci U S A. 1991; 88: 7430-7433Crossref PubMed Scopus (213) Google Scholar Because VLA-4 is not found on the surface of neutrophils, we have proposed that IL-4 (or IL-13) activation of VCAM-1 expression may be one mechanism by which selective recruitment of eosinophils occurs. According to our experiments, those of several other laboratories,26Schleimer RP Freeland HS Peters SP Brown KE Derse CP An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelial cells and formation of leukotriene B4 by purified human neutrophils.J Pharmacol Exp Ther. 1989; 250: 598-605PubMed Google Scholar, 27Bochner BS Peachell PT Brown KE Schleimer RP Adherence of human basophils to cultured umbilical vein vascular endothelial cells.J Clin Invest. 1988; 81: 1355-1360Crossref PubMed Scopus (55) Google Scholar, 28Kaiser J Bickel C Bochner BS Schleimer RP The effects of the potent glucocorticoid budesonide on adhesion of eosinophils to human vascular endothelium and on endothelial expression of adhesion molecules.J Pharmacol Exp Ther. 1993; 267: 245-249PubMed Google Scholar, 29Moser R Schleiffenbaum B Groscurth P Fehr J Interleukin 1 and tumor necrosis factor stimulate human vascular endothelial cells to promote transendothelial neutrophil passage.J Clin Invest. 1989; 83: 444-455Crossref PubMed Scopus (262) Google Scholar and personal communications with Dr. Colin Dunn, Upjohn; Dr. John White, Smithkline Beecham; and Dr. Jordan Pober, Yale University; steroid treatment of endothelial cells before stimulation with these cytokines does not inhibit the expression or function of these adhesion molecules. Steroids failed to inhibit neutrophil or basophil adhesion to endothelial cells stimulated by either endothelial activators or leukocyte activators.26Schleimer RP Freeland HS Peters SP Brown KE Derse CP An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelial cells and formation of leukotriene B4 by purified human neutrophils.J Pharmacol Exp Ther. 1989; 250: 598-605PubMed Google Scholar, 27Bochner BS Peachell PT Brown KE Schleimer RP Adherence of human basophils to cultured umbilical vein vascular endothelial cells.J Clin Invest. 1988; 81: 1355-1360Crossref PubMed Scopus (55) Google Scholar In contrast, Cronstein et al.30Cronstein BN Kimmel SC Levin RI Martiniuk F Weissmann G A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1.Proc Natl Acad Sci U S A. 1992; 89: 9991-9995Crossref PubMed Scopus (659) Google Scholar reported that steroids inhibit endothelial E-selectin expression. The reason for the disparity of results between Cronstein et al.30Cronstein BN Kimmel SC Levin RI Martiniuk F Weissmann G A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1.Proc Natl Acad Sci U S A. 1992; 89: 9991-9995Crossref PubMed Scopus (659) Google Scholar and others is unknown. Recent studies showed no inhibition of eosinophil adhesion to endothelial cells induced by IL-4 or other endothelial activators or by leukocyte activators, including platelet activating factor (PAF) and fmet-peptide.28Kaiser J Bickel C Bochner BS Schleimer RP The effects of the potent glucocorticoid budesonide on adhesion of eosinophils to human vascular endothelium and on endothelial expression of adhesion molecules.J Pharmacol Exp Ther. 1993; 267: 245-249PubMed Google Scholar Culture of eosinophils with GM-CSF or other cytokines dramatically increases adhesion, transendothelial migration, and expression of the adhesion molecule CD11b in response to chemoattractants such as PAF or fmet-peptide.31Lopez AF Sanderson CJ Gamble JR Campbell HD Young IG Vadas MA Recombinant human interleukin 5 is a selective activator of human eosinophil function.J Exp Med. 1988; 167: 219-224Crossref PubMed Scopus (808) Google Scholar, 32Yamaguchi Y Hayashi Y Sugama Y et al.Highly purified murine interleukin 5 (IL-5) stimulates eosinophil function and prolongs in vitro survival.J Exp Med. 1988; 167: 1737-1742Crossref PubMed Scopus (564) Google Scholar, 33Walsh GM Hartnell A Wardlaw AJ Kurihara K Sanderson CJ Kay AB IL-5 enhances the in vitro adhesion of human eosinophils, but not neutrophils, in a leucocyte integrin (CD11/18)-dependent manner.Immunology. 1990; 71: 258-265PubMed Google Scholar, 34Tomioka K MacGlashan Jr, DW Lichtenstein LM Bochner BS Schleimer RP GM-CSF regulates human eosinophil responses to F-Met peptide and platelet activating factor.J Immunol. 1993; 151: 4989-4997PubMed Google Scholar, 35Ebisawa M Liu MC Yamada T et al.Eosinophil transendothelial migration induced by cytokines. II. The potentiation of eosinophil transendothelial migration by eosinophil-active cytokines.J Immunol. 1994; 152: 4590-4597PubMed Google Scholar Steroids did not inhibit the increase in adhesion molecule expression or changes in intracytoplasmic calcium, which followed activation with chemoattractants.34Tomioka K MacGlashan Jr, DW Lichtenstein LM Bochner BS Schleimer RP GM-CSF regulates human eosinophil responses to F-Met peptide and platelet activating factor.J Immunol. 1993; 151: 4989-4997PubMed Google Scholar Glucocorticoids are known to be potent inhibitors of the release of factors that activate endothelium including IL-1, TNF, IL-4, (and we expect IL-13), and leukocytes (e.g., chemokines; see Table I). Thus although they do not appear to directly inhibit activation of eosinophils or endothelial cells by these factors, it is anticipated that steroids inhibit activation of eosinophils and endothelial cells indirectly by depressing the generation of these cytokines. TABLE IThe effect of glucocorticoids on production of cytokines relevant to eosinophil recruitment and activationCytokineRelevant actionEffect of glucocorticoids on synthesisReferenceEndothelial activators IL-1, TNF-αInduce E-selectin, VCAM-1, and ICAM-1; induce chemokine releaseInhibition125, 128, 134, 135, 136 IL-4Induces VCAM-1 expressionInhibition93, 131, 132, 137 IL-13Induces VCAM-1 expressionUnknownEosinophil activators IL-3, IL-5, GM-CSFPrime eosinophil responses; prolong eosinophil survivalInhibition14, 87-91, 93, 132 RANTES, MIP-1α,Eosinophil chemoattractantInhibition43, 138 MCP-2, MCP-3, eotaxinEosinophil chemoattractantUnknown LCFEosinophil chemoattractantUnknown Open table in a new tab We recently participated in the 5th International Conference on Human Leukocyte Differentiation Antigens in which CD designations are assigned. We screened approximately 475 monoclonal antibodies for reactivity toward purified human eosinophils.36Ebisawa M Schleimer RP Bickel C Bochner BS Phenotyping of purified human peripheral blood eosinophils using the blind panel of monoclonal antibodies.in: Leukocyte typing V: white cell differentiation antigens. : Oxford University Press, Oxford1994Google Scholar Of these, 350 were negative. We prepared 35 pools, each containing 10 negative antibodies, and screened for increased staining in eosinophils cultured overnight in the presence of either medium alone or the potent steroid budesonide. Unfortunately, budesonide failed to induce expression of negative markers detectable with the pooled antibodies (C. Bickel et al. Unpublished observations). Glucocorticoid treatment in vivo (24 hours) has been shown by Clark et al.37Clark RAF Gallin JI Fauci AS Effects of in vivo prednisone on in vitro eosinophil and neutrophil adherence and chemotaxis.Blood. 1979; 53: 633-641PubMed Google Scholar to lead to inhibition of the migration of eosinophils subsequently tested in vitro. However, Altman et al.38Altman LC Hill JS Hairfield WM Mullarkey MF Effects of corticosteroids on eosinophil chemotaxis and adherence.J Clin Invest. 1981; 67: 28-36Crossref PubMed Scopus (94) Google Scholar found no effect on eosinophil chemotaxis 4 hours after steroid administration. Because glucocorticoids may lead to alterations in subsets of eosinophils, as seen with lymphocytes and basophils, it is difficult to interpret the results of in vivo studies. As observed with human neutrophils, in vitro studies indicate that eosinophils are resistant to effects of glucocorticoids on chemotaxis. Kurihara et al.39Kurihara K Wardlaw AJ Moqbel R Kay AB Inhibition of platelet-activating factor (PAF)-induced chemotaxis and PAF binding to human eosinophils and neutrophils by the specific ginkgolide-derived PAF antagonist BN 52021.J ALLERGY CLIN IMMUNOL. 1989; 83: 83-90Abstract Full Text PDF PubMed Scopus (45) Google Scholar reported that incubation of purified human eosinophils with steroid for up to 6 hours has no effect on migration of eosinophils in response to PAF in vitro. Although Prin et al.5Prin L Lefebvre PP Gruart V et al.Heterogeneity of human eosinophil glucocorticoid receptor expression in hypereosinophilic patients: absence of detectable receptor correlates with resistance to corticotherapy.Clin Exp Immunol. 1989; 78: 383-389PubMed Google Scholar claimed that steroids induce a modest inhibition of chemotaxis, the concentration of dexamethasone used was rather high (4 × 10–6 mol/L). Although glucocorticoids may not inhibit the chemotactic cellular response itself (i.e., either actual cell motility or the expression of adhesion molecules on either eosinophils or endothelium), glucocorticoids are powerful and specific inhibitors of the release of most members of the families of inflammatory mediators that induce both chemotaxis and adhesion (e.g., PAF,40Andersson P Chignard M Brange C Nilsson T Juhlin M Le-Couedic JP Effect of glucocorticosteroid treatment on antigen-induced mediator release from sensitized guinea pig lungs.in: Glucocorticoids, inflammation, and bronchial hyperreactivity. : Excerpta Medica, Amsterdam1985: 132-135Google Scholar leukotriene B4,41Flower RJ Glucocorticoids and the inhibition of phospholipase A2.in: Anti-inflammatory steroid action. Basic and clinical aspects. : Academic Press, San Diego1989: 48-66Google Scholar peptides including members of the chemokine family,42Wertheim WA Kunkel SL Standiford TJ et al.Regulation of neutrophil-derived IL-8: the role of prostaglandin E2 dexamethasone, and IL-4.J Immunol. 1993; 151: 2166-2175PubMed Google Scholar especially RANTES,43Stellato C Beck LA Schall TJ Proud D Ono SJ Schleimer RP Expression of the chemokine RANTES in human epithelial cells.FASEB J. 1994; 8 ([Abstract]): A225Google Scholar monocyte chemotactic protein-3 and eotaxin, and chemotactic hematopoietic cytokines such as IL-5,14Rolfe FG Hughes JM Armour CL Sewell WA Inhibition of interleukin-5 gene expression by dexamethasone.Immunology. 1992; 77: 494-499PubMed Google Scholar lymphocyte chemotactic factor [LCF], and others). No information is yet available on the effects of glucocorticoids on the release of MCP-3, eotaxin, or LCF; in all of the other cases mentioned above, glucocorticoids are potent and effective inhibitors of their release. Thus it is anticipated that in vivo treatment with steroids can inhibit eosinophil migration indirectly by decreasing or completely preventing the production of chemoattractants for eosinophils. Howe et al.44Howe RS Lee YH Fischkoff SA Teuscher C Lyttle CR Glucocorticoid and progestin regulation of eosinophil chemotactic factor and complement C3 in the estrogen-treated rat uterus.Endocrinology. 1990; 126: 3193-3199Crossref PubMed Scopus (28) Google Scholar have shown that glucocorticoids inhibit the release of a uterus-derived eosinophil chemotactic factor suspected to be involved in eosinophil infiltration during estrus. Another example, more relevant to allergic diseases of the airways, is the effect of steroids on release and production of the chemokine RANTES from epithelial cells. Recent immunohistochemical studies have identified epithelium as a primary source of this eosinophil chemotactic chemokine.45Beck LA Schall TJ Beall LD et al.Detection of the chemokine RANTES and activation of vascular endothelium in nasal polyps.J ALLERGY CLIN IMMUNOL. 1994; 93 ([Abstract]): 234Google Scholar Studies in nasal polyps, nasal biopsy specimens, and human central airways have all shown epithelial cell production of RANTES. In vitro studies have established that glucocorticoids inhibit epithelial production of RANTES dramatically.43Stellato C Beck LA Schall TJ Proud D Ono SJ Schleimer RP Expression of the chemokine RANTES in human epithelial cells.FASEB J. 1994; 8 ([Abstract]): A225Google Scholar Thus the epithelium on the one hand appears to be the source of chemoattractants, which ultimately lead to the migration of eosinophils and destruction of airway epithelium. On the other hand, epithelium, which is an immediate target of topically applied steroids in either the nose or lungs, appears to be extremely susceptible to the profound suppressive effects of glucocorticoids on the release of the RANTES chemoattractant. The effects of glucocorticoids on degranulation vary among different cell types (e.g., glucocorticoids inhibit degranulation of human basophils, rat mast cells, and rat basophilic leukemia cells but not human mast cells).46Schleimer RP The effects of glucocorticoids on mast cells and basophils.in: Anti-inflammatory steroid action. 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In the latter case, steroids did not inhibit immunoglobulin-induced degranulation of eosinophils that had been primed by cytokines. These findings are similar to results of studies in human neutrophils in which dexamethasone failed to inhibit degranulation or leukotriene B4 release.26Schleimer RP Freeland HS Peters SP Brown KE Derse CP An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelial cells and formation of leukotriene B4 by purified human neutrophils.J Pharmacol Exp Ther. 1989; 250: 598-605PubMed Google Scholar One of the rapidly emerging areas in biology in general and in the study of inflammatory cells in particular is the study of programmed cell death, which results in apoptosis.50Cohen JJ Duke RC Apoptosis and programmed cell death in immunity.Annu Rev Immunol. 1992; 10: 267-293Crossref PubMed Scopus (1105) Google Scholar, 51Williams GT Smith CA Molecular regulation of apoptosis: genetic controls on cell death.Cell. 1993; 74: 777-779Abstract Full Text PDF PubMed Scopus (903) Google Scholar, 52Vaux DL Haecker G Strasser A An evolutionary perspective on apoptosis.Cell. 1994; 76: 777-779Abstract Full Text PDF PubMed Scopus (689) Google Scholar In contrast to necrotic cell death, apoptosis is characterized by defined changes such as condensation of chromatin and the nucleus, shrinkage of the cell, expression of as yet incompletely understood adhesion molecules on the cell surface that facilitate engulfment, and the orderly destruction of the apoptotic cell by phagocytic cells in vivo. Also associated with apoptosis is a destruction of cellular DNA by endonucleases, which cleave in the internucleosomal regions forming a "laddering" of DNA. All types of circulating granulocytes appear to be programmed for cell death, and when cultured in the absence of enriched medium, die rather quickly. In vitro, granulocytes undergo phagocytosis by macrophage-like cells through a process that appears to involve the vitronectin receptor on the phagocytic cells and unknown ligands on the apoptotic leukocyte.53Stern M Meagher L Savill J Haslett C Apoptosis in human eosinophils. 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