Ibuprofen Affects Pro- and Anti-Inflammatory Cytokine Production by Mononuclear Cells of Preterm Newborns

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The in vitro effect of indomethacin (IM) and ibuprofen (IB) on the production of the interleukin-1 receptor antagonist (IL-1ra) by cord blood mononuclear cells (CBMC) from preterm newborns was compared to that of peripheral blood mononuclear cells (PBMC) from adults. Mononuclear cells (MC) were incubated with lipopolysaccharide (LPS) in the absence or presence of various concentrations of IM and IB. The level of IL-1ra in the supernatants was tested by ELISA. The results showed a lower ability of MC from preterm newborns to produce IL-1ra as compared with adult cells, supporting the assumption of neonatal immune cell immaturity. IM at pharmacological concentrations caused inhibition of IL-1ra secretion by PBMC from adults whereas IB suppressed the secretion of IL-1ra at higher concentrations only. At the same concentrations neither drug had an in vitro effect on the production of IL-1ra by CBMC of preterm newborns. In conclusion, the lower ability of CBMC of preterm newborns to produce IL-1ra in response to LPS and the absence of an IM and IB effect on the secretion of this cytokine by these cells as compared with PBMC of adults, suggest an underdevelopment of the immune response in preterm newborns.

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Indomethacin and Ibuprofen Effect on IL-1ra Production by Mononuclear Cells of Preterm Newborns and Adults

Bessler

Ziyada²,

Bergman³

et al. 2002

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“…These findings are supported by previous reports indicating that neonatal MC differ from those of adults in cytokine profile and sensitivity to the in vitro effect of drugs on cytokine production [28][29][30][31][32][33][34] .…”

Section: Discussionsupporting

confidence: 90%

A Comparison of the Effect of Vitamin A on Cytokine Secretion by Mononuclear Cells of Preterm Newborns and Adults

Bessler¹,

Wyshelesky²,

Osovsky³

et al. 2006

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Background: For a long time vitamin A has been known to be essential for immune defense of the organism and protection against infections. Vitamin A deficiency in children is associated with morbidity and mortality from infectious diseases which could be prevented and even alleviated by vitamin A supplementation. Moreover, this vitamin is involved in the modulation of immunological and inflammatory responses by regulation of cytokine production. The aim of the study was to compare the in vitro effect of vitamin A on the production of pro-inflammatory (IL-1β and IL-6) and anti-inflammatory (IL-1 receptor antagonist (ra) and IL-10) cytokines, as well as IL-2 and IFNγ by cord blood mononuclear cells (CBMC) of preterm newborns to that of peripheral blood mononuclear cells (PBMC) from adults. Methods: Mononuclear cells (MC) from individuals of the two age groups were incubated with vitamin A (retinyl palmitate) at various concentrations in the presence of phytohemagglutinin for IL-2 and IFNγ production or LPS for IL-1β, IL-1ra, IL-6 and IL-10 secretion. The level of the cytokines in the supernatants was tested by ELISA. Results: Vitamin A exerted an in vitro inhibitory effect on the production of the anti-inflammatory cytokine IL-1ra by MC of preterm newborns and adults, but did not affect the secretion of the pro-inflammatory cytokines IL-1β, IL-6 and IFNγ. Vitamin A caused inhibition of IL-10 secretion by cells from adults, but it did not significantly affect this function in cells from newborns except when high unphysiological doses were applied. In addition vitamin A stimulated the secretion of IL-2 by cells isolated from adults but had no effect on those derived from premature neonates. Conclusions: The results indicate that vitamin A may affect the immune function of premature infants via inhibition of IL-1ra secretion. It is suggested that the beneficial effect of vitamin A on the clinical course of bronchopulmonary dysplasia (BPD) may be due to the reduced production of anti-inflammatory cytokines by neonatal CBMC. This may indicate the importance of the pro-inflammatory cytokines in the management of severe lung diseases and BPD.

“…However, many recent reports have shown specifi c proinfl ammatory effects of ibuprofen. For example, ibuprofen increases TNF-· and IL-6 production by splenic macrophages and neonatal mononuclear cells, decreases IL-10 production, and contributes to the accumulation of macrophages in injured tissues [20][21][22] . Ibuprofen promotes random migration of neutrophils and does not inhibit respiratory burst activity [16,[23][24][25][26] .…”

Section: Discussionmentioning

confidence: 99%

Effects of Ibuprofen and Hypoxia on Neutrophil Apoptosis in Neonates

Hanna

Graboski

Laskin³

et al. 2004

Background: Ibuprofen is a cyclooxygenase inhibitor that is effective in treating patent ductus arteriosus in preterm infants. However, recent trials have suggested that it may increase the risk of developing necrotizing enterocolitis and chronic lung disease. Apoptosis of neutrophils is impaired in newborns, leading to reduced clearance of activated cells and possibly contributing to the susceptibility of infants to these inflammatory diseases. Objectives: In the present studies, we investigated the hypothesis that ibuprofen reduces neonatal neutrophil apoptosis in the setting of hypoxia or lipopolysaccharide (LPS). Methods: Neutrophils and peripheral blood mononuclear cells were isolated from adult and cord blood and cultured in the presence or absence of ibuprofen (1.5 mM), hypoxia (<5% O₂), and bacterial LPS (100 ng/ml). Apoptosis was quantified by measuring binding of FITC-Annexin V using flow cytometry. Cytokine concentrations in cell supernatants were measured by ELISA. Results: After 24 h, 20% of adult and 14% of neonatal neutrophils were apoptotic. Apoptosis was reduced by hypoxia in both adult and neonatal cells. Ibuprofen further reduced neutrophil apoptosis, but only when the cells were cultured in the presence of mixed leukocytes. This suggests that the effects of ibuprofen on apoptosis are dependent on soluble products secreted by peripheral blood mononuclear cells. We found that production of tumor necrosis factor (TNF)-α by neonatal leukocytes was significantly increased by ibuprofen, and was further increased following exposure to ibuprofen in the presence of LPS and hypoxia. In contrast, production of macrophage inflammatory protein (MIP)-1α was not affected by treatment with ibuprofen, and ibuprofen blocked induction of this chemokine by LPS. Conclusion: We conclude that the net effect of ibuprofen on neutrophils is antiapoptotic, especially in the presence of hypoxia or LPS. This effect may be mediated, in part, by increased production of TNF-α by peripheral blood mononuclear cells. These data suggest that treatment of infants with ibuprofen, in the presence of infection and/or tissue hypoperfusion/hypoxia, may contribute to the development of inflammatory diseases.