Cytokine profiles of cord and adult blood leukocytes: differences in expression are due to differences in expression and activation of transcription factors

Theresa Clauss,Andreas Nitsche,Meixia Zhang,Andreas Pahl,Wolfgang Siegert,Kay Brune

doi:10.1186/1471-2172-8-18

Abstract

BackgroundStem cell transplantation as therapy for hematological disorders is often hampered by severe graft-versus-host-disease. This may be reduced by umbilical cord blood transplantation, an effect that has been attributed to qualitative differences between neonatal and adult T cells. We compared levels of secreted proteins and cytokine mRNA induced in cord blood leukocytes (CBL) and adult blood leukocytes (ABL) by various stimuli.ResultsWhile interleukin-2 (IL-2) levels were similar in CBL and ABL, there was less induction of the Th1 cytokine interferon-γ in CBL. Production of the Th2 cytokines IL-4, IL-5, and IL-13 and the hematopoietic cytokine IL-3 was much lower in CBL versus ABL after T-cell receptor-mediated stimulation, whereas production of GM-CSF was comparable in the 2 cell types. The lower levels of Th1 and Th2 cytokines were maintained in CBL during a 4-day time-course study, while after 12 hours IL-3 and GM-CSF reached in CBL levels similar to those in ABL. For all cytokines except IFNγ, the IC50 values for inhibition by cyclosporin A were similar in ABL and CBL. In contrast, there was less expression and activation of transcription factors in CBL. Activation of NF-κB by TPA/ionomycin was detected in ABL but not CBL. Furthermore, there was less expression of the Th subset-specific transcription factors T-bet and c-maf in CBL versus ABL, whereas GATA-3 expression was similar. Expression of T-bet and c-maf correlated with expression of the Th1 and Th2 cytokines, respectively. Time course experiments revealed that T-bet expression was stimulated in both cell types, whereas c-maf and GATA-3 were induced only in ABL.ConclusionThe diminished capability of CBL to synthesize cytokines is probably due to decreased activation of NF-κB, whereas differences in Th subsets are due to differences in regulation of Th lineage-specific transcriptions factors. We propose that the reduced incidence and severity of GvHD after allogeneic transplantation of umbilical CB cells is due to lesser activation of specific transcription factors and a subsequent reduction in production of certain cytokines.

Highlights

Stem cell transplantation as therapy for hematological disorders is often hampered by severe graft-versus-host-disease
The diminished capability of cord blood leukocytes (CBL) to synthesize cytokines is probably due to decreased activation of NF-κB, whereas differences in Th subsets are due to differences in regulation of Th lineage-specific transcriptions factors
We propose that the reduced incidence and severity of graft-versus-host disease (GvHD) after allogeneic transplantation of umbilical cord blood (CB) cells is due to lesser activation of specific transcription factors and a subsequent reduction in production of certain cytokines

Summary

Introduction

Stem cell transplantation as therapy for hematological disorders is often hampered by severe graft-versus-host-disease. This may be reduced by umbilical cord blood transplantation, an effect that has been attributed to qualitative differences between neonatal and adult T cells. Despite major HLA differences, the graft failure rate and incidence and severity of graft-versus-host disease (GvHD) are low [3,4]. The reasons for this are still unknown. The incidence and severity of GvHD may be sensitive to factors relevant to transplantation such as HLA compatibility, donor and recipient age, T-cell inoculum, and the source of stem cells and to the effects of a number of cytokines. It is important to investigate whether differences in cytokine production between CB and AB can account in part for the reduced incidence of graft versus host disease with CB transplantation

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