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Decreased interleukin-12 (IL-12) from activated cord versus adult
peripheral blood mononuclear cells and upregulation of interferon- gamma,
natural killer, and lymphokine-activated killer activity by IL- 12 in cord
blood mononuclear cells
SM Lee, Y Suen, L Chang, V Bruner, J Qian, J Indes, E Knoppel, C van de Ven and MS Cairo
Division of Hematology/Oncology and Blood and Bone Marrow Transplantation,
Children's Hospital of Orange County, CA 92668, USA.
Interleukin-12 (IL-12) is a critical cytokine regulating natural killer
(NK) and T-cell function. We hypothesized that the impaired ability of cord
blood (CB) to produce normal adult levels of IL-12 in response to
stimulation may contribute to the immaturity of CB immunity. Furthermore,
exogenous IL-12 may compensate for the immaturity in CB cellular immunity
and have the potential for immunotherapy post cord blood transplantation.
We compared the expression and production of IL- 12 from activated cord
versus adult mononuclear cells (MNC), regulatory mechanisms associated with
IL-12 expression in CB MNC, and the effects of IL-12 on induction of CB
interferon (IFN)-gamma production, NK, and lymphokine-activated killer
(LAK) cytotoxicity. Northern analysis and enzyme-linked immunosorbent assay
were performed in lipopolysaccharide (LPS)-stimulated CB and adult
peripheral blood (APB) MNC. IL-12 mRNA expression was induced within 6
hours with LPS (10 micrograms/ml) and reached peak levels at 12 hours in
both CB and APB MNC. However, IL-12 mRNA expression and protein
accumulation in CB MNC were 35.8% +/- 4.84% (12 hours, n = 11, P < .05),
and 17.6% +/- 1.7% (24, 72, 96 hours, n = 9, P < .05) respectively, when
compared with APB MNC. Nuclear run-on assays showed no differences between
CB and APB MNC in both the basal levels of transcription and the degree of
transcriptional activation. However, the half-life of IL-12 p40 mRNA was
approximately threefold lower in activated CB MNC than in activated APB MNC
(CB: 114 +/- 3.0 minutes v APB: 353 +/- 7.8 minutes, n = 3, P < .05).
Exogenous IL-12 (10 U/mL) induced a significant increase of IFN-gamma from
both CB and APB MNC (24 hours, 72 hours, P < .05, n = 3). The stimulated
CB IFN- gamma level reached comparable levels produced by unstimulated APB.
IL- 12 treatment also significantly enhanced CB NK cytotoxicity against
K562 and NB-100 cell lines to the comparable levels of APB (P < .05, n =
4). CB MNC was more responsive to IL-12 stimulation with respect to
IFN-gamma production, NK, and LAK cytotoxicity when compared with APB. The
present study suggests that IL-12 mRNA and protein expression is decreased
in activated CB. This discrepancy in IL-12 production is secondary, at
least in part, to the altered posttranscriptional regulation. The impaired,
ability of CB MNC to produce IL-12 in response to stimulation may
contribute to the decrease in IFN-gamma production and NK cytotoxicity.
However, IL-12 enhanced IFN-gamma and NK activity in CB MNC up to the
comparable levels of APB MNC. These findings suggest that reduced
expression and production of IL-12 from activated CB may contribute to the
immaturity in CB cellular immunity and contribute, in part, to decreased
graft-versus-host disease following CB stem cell transplantation.
Volume 88,
Issue 3,
pp. 945-954,
08/01/1996
Copyright © 1996 by The American Society of Hematology
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