Kortikoide schützen Oligodendrozyten-Vorläuferzellen vor Zytokin-induzierten Schäden

Zusammenfassung

Es gibt immer mehr Hinweise darauf, dass eine aszendierende intrauterine Infektion mit einem erhöhten Risiko einer periventrikulären Leukomalazie (PVL) bei frühgeborenen Kindern verbunden ist. Eine akute Störung der Myelinisierung, begründet in einem Verlust von Oligodendrozyten-Vorläuferzellen, ist ein charakteristisches Merkmal der PVL. Wir konnten bereits zeigen, dass die entzündlichen Zytokine Interferon-γ (IFN-γ) und Tumor Nekrose Faktor-α (TNF-α) in Oligodendrozyten-Vorläuferzellen zum einen Apoptose induzieren und zum anderen die Differenzierung zu reifen myelinisierenden Oligodendrozyten verhindern. In der vorliegenden Studie wurden die Kortikosteroide Kortikosteron, Deoxykortikosteron und Dexamethason auf einen möglichen protektiven Effekt vor diesen Zytokin-induzierten Schädigungen hin untersucht. Wir konnten zeigen, dass im Vergleich zu Zytokin-behandelten Kulturen eine gleichzeitige Behandlung mit Kortikosteroiden zum einen zu einer erhöhten Gesamtzellzahl am Kulturtag 9 führte. Zum anderen zeigten Western-Blot-Analysen, semiquantitative RT-PCR und Immunzytochemie deutlich, dass Kortikosteroide die Zytokin-induzierte Hemmung der Differenzierung von Oligodendrocyten-Vorläuferzellen abschwächen. Kortikosteroide schützen demnach Oligodendrozyten-Vorläuferzellen vor Zytokin-induzierten Schäden.

Abstract

In preterm fetuses an ascending intrauterine inflammation before or during birth can be associated with periventricular leukomalacia (PVL). PVL is characterised by a disrupted. myclination. due to a loss of oligodendrocyte progenitors. Inflammatory cytokines not only induce apoptotic cell death but in addition prevent the differentiation of the immature A2B5 oligodendrocytc progenitors into the myelinating phenotype. The aim of the present study was to clarify whether corticosteroids can protect oligodendrocyte progenitors from such injury.
Cultuxes of more than 90 % A2B5 positive progenitors were prepared from neonatal sprague dawley rats. After 1 day in proliferation medium, cells were treated with interferon- (IFN-γ; 10 U/ml) and tumour necrosis factor- (TNF-α; 10 ng/ml) for 48 h. In Addition, corticosterone (C), deoxycorticosterone (DC), or dexamethasone (DEX) (1 µM) were applied to the incubation medium of the study groups_ After treatment cultures were transferred to media containing factors to promote differentiation of progenitors into thc myelinating phenotype. At culture day 9 total teil number was deterrmined. In addition, cells were analysed by immunocytochemistry for A2B5 as well. as by RTPCR and western-blot-analysis of chic myelin-specific protcins MBP, MAG and CNP.
Application of INF-γ and TNF-α caused a dramatic decrease in. cell nurnber at culture day 9. More than 30 % of the surviving cells were A2B5-positive compared to 1 % in control dishes. Protein expression of MBP, MAG and CNP as well as mRNA expression, of MAG and MBP were considerably reduced after administration of INF- and TNF-. Co-treatment with, corticosteroids significantly increased total cell count, dexamethasone showing the strongest protective effect.Moreover, corticosteroids al l.evi.ated the cytokine induced inbibition in protein- and mRNAexpression of MBP, MAG and CNP.
Corticosteroids therefore protect oligodendrocyte progenitors from cytokine-induced cell damage.

Schlüsselwörter

Periventrikuläre Leukomalazie - Tumor Nekrose Faktor-alpha - Interferon-gamma - Kortikoide

Key words

Periventricular leukomalacia - tumour necrosis factor-alpha - interferon-gamma - corticosteroids

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