Effects of Dexamethasone on IL-1β, IL-6, and TNF-α Production by Mononuclear Cells of Newborns and Adults

Bessler, Hanna; Mendel, Carl M.; Straussberg, R; Gurary, Natalia M.; Aloni, D.; Sirota, Lea

doi:10.1159/000014099

Cited by 39 publications

(25 citation statements)

References 24 publications

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“…These results support the relevance of the IL-8 concentration in whole blood as a sensitive marker of cytokine production, which may be superior to the measurement of serum levels. Dexamethasone inhibits lipopolysaccharide-induced IL-6 production, as well as IL-8 release from mononuclear and/or neutrophil cells in neonates (4,20). We were not able to assess the effect of antenatal steroids on spontaneous IL-8 production in relation to labor because of the relatively small number of spontaneously delivered preterm infants.…”

Section: Discussionmentioning

confidence: 96%

Cell-Associated Interleukin-8 in Cord Blood of Term and Preterm Infants

Dembinski¹,

Behrendt²,

Heep³

et al. 2002

Clin Vaccine Immunol

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To assess the effect of gestational age and labor on the interleukin-8 (IL-8) concentration in whole cord blood and serum, IL-8 levels were determined simultaneously in cord blood serum and lysate in 134 infants. Following the elimination of some of the samples due to exclusion criteria, the data for 99 uninfected infants (71 term and 28 preterm) and 9 infants with neonatal bacterial infection delivered either vaginally or by elective or emergency cesarean section were analyzed. The effects of labor and gestational age were tested by analysis of variance. IL-8 was not detectable in the serum of 25 infants, whereas IL-8 levels in whole blood were measurable in all of the samples. The median IL-8 conncentrations in whole cord blood lysate were 106 pg/ml (range, 20 to 415 pg/ml) in preterm infants and 176 pg/ml (range, 34 to 1,667 pg/ml) in term infants. In contrast to the IL-8 levels in serum, IL-8 levels in whole blood were reduced after ECS. Gestational age had no independent effect on the IL-8 concentrations in either serum or whole blood; these concentrations increased in infected infants after labor. We conclude that the neonatal proinflammatory response to labor stress was more evident in the concentrations of IL-8 in whole blood than in serum. The levels of IL-8 in whole-blood lysate reflect proinflammatory stimulation in neonates and may be a useful diagnostic tool for the early diagnosis of neonatal infection.Interleukin-8 (IL-8) belongs to the class of proinflammatory "CC" chemokines defined by the position of two cysteine groups and is synthesized predominantly by monocytes. Its active form effectively activates neutrophil granulocytes, advancing the chemotaxis and synthesis of myeloperoxidase, thus suggesting a critical role in host defense to infectious diseases (1, 2).The IL-8 concentration in serum has been studied as a diagnostic marker of neonatal bacterial infection (NBI) (10, 11) and has been shown to be an early marker of neonatal bacterial infection, whereas the concentration of C-reactive protein (CRP) increases after 12 to 24 h in the course of systemic infectious disease. A "diagnostic gap " exists between the decline of IL-8 after 4 to 6 h and the increase in C-reactive protein at 12 to 24 h, which is a well-established marker of confirmed bacterial infection. Due to the rapid serum clearing of IL-8, its value as a monitoring parameter of infectious disease may be limited. In vivo, a large proportion of IL-8 is associated with erythrocytes and leukocytes (polymorphonuclear leukocytes and peripheral blood mononuclear cells), and the concentration in serum represents only a small fraction of the total amount of IL-8. The measurement of cell-associated IL-8 reflects more quantitatively its production and adds information regarding the stage of the disease and the patient's inflammatory response (7,9,13,14). Total IL-8 can be measured in whole blood after cell lysis with a good analytical test (16). In healthy adults, we previously observed an IL-8 peak level of Ͻ12 pg/ml with a median of 83 p...

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Section: Discussionmentioning

confidence: 96%

Cell-Associated Interleukin-8 in Cord Blood of Term and Preterm Infants

Dembinski¹,

Behrendt²,

Heep³

et al. 2002

Clin Vaccine Immunol

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“…First, estradiol and progesterone strongly inhibited TNF and IL-6 production induced by purified microbial products as well as E. coli and GBS in CBMCs and/or purified newborn monocytes. Second, estradiol and progesterone at relevant physiologic concentrations were as potent inhibitors of cytokine production as hydrocortisone, an endogenous glucocorticoid with well-known anti-inflammatory properties (4,44). Third, CBMCs and newborn monocytes were more sensitive to the anti-inflammatory effects of estradiol and progesterone than adult PBMCs and monocytes.…”

Section: Discussionmentioning

confidence: 99%

Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns

et al. 2011

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Newborns are particularly susceptible to bacterial infections due to qualitative and quantitative deficiencies of the neonatal innate immune system. However, the mechanisms underlying these deficiencies are poorly understood. Given that fetuses are exposed to high concentrations of estradiol and progesterone during gestation and at time of delivery, we analyzed the effects of these hormones on the response of neonatal innate immune cells to endotoxin, bacterial lipopeptide, and Escherichia coli and group B Streptococcus, the two most common causes of early-onset neonatal sepsis. Here we show that at concentrations present in umbilical cord blood, estradiol and progesterone are as powerful as hydrocortisone for inhibition of cytokine production by cord blood mononuclear cells (CBMCs) and newborn monocytes. Interestingly, CBMCs and newborn monocytes are more sensitive to the effects of estradiol and progesterone than adult peripheral blood mononuclear cells and monocytes. This increased sensitivity is associated with higher expression levels of estrogen and membrane progesterone receptors but is independent of a downregulation of Toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation primary response gene 88 in newborn cells. Estradiol and progesterone mediate their anti-inflammatory activity through inhibition of the NF-B pathway but not the mitogenactivated protein kinase pathway in CBMCs. Altogether, these results suggest that elevated umbilical cord blood concentrations of estradiol and progesterone acting on mononuclear cells expressing high levels of steroid receptors contribute to impair innate immune responses in newborns. Therefore, intrauterine exposure to estradiol and progesterone may participate in increasing susceptibility to infection during the neonatal period.Newborns are at high risk of severe bacterial infections. Early-onset neonatal sepsis occurs during the first week of life in 1 to 5 per 1,000 births (14,24,25). Group B Streptococcus (GBS) and Escherichia coli are involved in more than 50% of episodes of early-onset neonatal sepsis. Despite antimicrobial therapy and improvements in neonatal intensive care, the mortality due to neonatal sepsis remains high (5 to 15%) and survivors are at risk of permanent neurologic damage (14,24,25). The particularly high susceptibility to infection during the neonatal period has been associated with quantitative and qualitative deficiencies of innate immunity (such as reduced levels of opsonins, decreased cytokine production, and impaired function of phagocytes) and adaptive immunity (such as impaired function of antigen-presenting cells and T cells and decreased production of immunoglobulins) (1,19,36). Although the differences between the neonatal and adult immune responses are relatively well described, the underlying mechanisms that account for the decreased ability of newborns to mount efficient immune responses remain largely unknown.Fetuses are chronically exposed to high levels of steroid hormones due to placental production. Concentrations ...

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“…Serum concentrations to 10 Ϫ5 mol may be reached pharmacologically (5). Cultures that were incubated in the absence of dexamethasone served as controls.…”

Section: Patientsmentioning

confidence: 99%

“…Mononuclear cells from adults and neonates respond differently to treatment with dexamethasone. With respect to proinflammatory cytokines, cord blood cells show an increased sensitivity toward the inhibitory action of dexamethasone compared with cells from adult donors, resulting in a more pronounced inhibition of IL-1␤, IL-6, tumor necrosis factor-␣, IL-12, IL-2, and IL-3 production (5,6).…”

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confidence: 99%

Effect of Dexamethasone on B7 Regulation and T Cell Activation in Neonates and Adults

et al. 2005

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The safety of dexamethasone for neonates has been questioned, partly because of its multiple unspecific effects on the immune system. Specific effects of dexamethasone on costimulatory and immune suppressive functions of neonatal compared with adult macrophages (M⌽) are not known. We evaluated the effect of dexamethasone on the expression and regulation of M⌽ B7 family receptors (B7-1, CD80; B7-2, CD86) and on their ability to co-stimulate T cells. Cord blood macrophages (CBM⌽) and M⌽ from healthy adults (PBM⌽) were isolated, and cell surface markers were phenotyped by flow cytometry. In tissue culture, cells were exposed to dexamethasone, interferon-␥ (IFN-␥), cAMP, or a T cell mitogen (␣CD3) and examined for their capacity to activate or destroy T cells. CBM⌽ were less able to up-regulate CD80 and CD86 than PBM⌽ (p Ͻ 0.05). Dexamethasone inhibited the up-regulation of CD80, CD86, and HLA-DR on PBM⌽ and even more so on CBM⌽ (p Ͻ 0.05 versus PBM⌽ for CD80 and CD86). In the presence of dexamethasone, stimulation with ␣CD3 MAb enhanced cytotoxic functions of PMBM⌽ and CB⌴⌽ with an increase in deleted T cells, a reduced fraction of enlarged T cells, and an inhibition of T cell CD28 up-regulation, which again were more pronounced with CBM⌽ (p Ͻ 0.05 versus PBM⌽). In conclusion, neonatal M⌽ are exquisitely sensitive to the inhibitory effects of dexamethasone on B7 expression. Although perhaps producing the desired therapeutic effect, dexamethasone may do so in newborns at the expense of a near complete paralysis of M⌽-dependent T cell function. Preterm newborns have been exposed to dexamethasone for the prevention or treatment of bronchopulmonary dysplasia (BPD) for many years (1,2). Dexamethasone is a synthetic glucocorticoid that reduces the recruitment of inflammatory cells (3,4) and thereby is thought to inhibit the development of BPD. Its effects on other developing organs such as the CNS were only recognized much later. Because follow up-studies provided evidence of abnormal neurodevelopment, early postnatal use of dexamethasone is not recommended any more (2). Nevertheless, glucocorticoids continue to be given to pregnant women to accelerate fetal lung development.Besides the endocrinium, the primary target of dexamethasone is the immune system, which is incompletely developed in neonates. Evidence that the immunosuppressive effects of dexamethasone are primarily mediated via an inhibition of cytokine production has been produced. Mononuclear cells from adults and neonates respond differently to treatment with dexamethasone. With respect to proinflammatory cytokines, cord blood cells show an increased sensitivity toward the inhibitory action of dexamethasone compared with cells from adult donors, resulting in a more pronounced inhibition of IL-1␤, IL-6, tumor necrosis factor-␣, 6).Dexamethasone may directly inhibit T cell proliferation (7), induce apoptosis (8), promote long-lasting changes in the T cell receptor v␤ repertoire (9), or decrease the CD4/CD8 ratio in infants with BPD (10). Dexamethasone also infl...

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Effects of Dexamethasone on IL-1β, IL-6, and TNF-α Production by Mononuclear Cells of Newborns and Adults

Cited by 39 publications

References 24 publications

Cell-Associated Interleukin-8 in Cord Blood of Term and Preterm Infants

Cell-Associated Interleukin-8 in Cord Blood of Term and Preterm Infants

Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns

Effect of Dexamethasone on B7 Regulation and T Cell Activation in Neonates and Adults

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