Distinct patterns of stimulus-inducible chemokine mRNA accumulation in human fetal astrocytes and microglia

Interferon-γ-inducible 10 kd protein (IP-10) is an ELR (Glu-Leu-Arg)- α chemokine with known chemotactic effects on T cells and monocytes, as well as anti-vital, anti-angiogenic, and anti-tumor effects. Previous studies have demonstrated that in cultured rat astrocytes and microglia, stimulation with LPS or virus can induce the expression of IP-10. In this study, we determined the pattern of IP-10 gene induction in primary human microglia and astrocytes by cytokines and LPS using ribonuclease protection assay. The expression of IP-10 mRNA was compared with that of other alpha (IL-8) and beta chemokines. The results showed that in human microglia, IP-10 expression was induced equally potently by LPS, IFNβ or IFNγ. 'Proinflammatory' cytokines IL-1β or TNFα also induced small amounts of IP-10 mRNA. 'Anti-inflammatory' cytokines IL-4, IL-10 and TGFβ were ineffective in inducing IP-10 in microglia. In human astrocytes, induction of IP-10 mRNA by cytokines was similar to that in microglia. LPS, however, was ineffective in inducing IP-10 in human astrocytes. The monocyte chemoattractant β-chemokine I-309 mRNA was induced in human astrocytes and microglia by IFNβ or IFNγ, or by LPS in microglia, showing a tight co-regulation with IP-10 mRNA expression. In contrast to the potent induction of IP-10 and 1-309 by IFNs in human glia, the ELR⁺ α chemokine IL-8 mRNA was induced by IL-1β and TNFα, and to a lesser extent by IFNβ in microglia. IFNβ but not IFNγ was effective in inducing the expression of β chemokines MIP-1α and MIP-1β in human microglia, with the levels of mRNA similar to those induced by IL-1β or TNFα. Neither MIP-1α nor MIP-1β mRNAs were induced by any stimulation in human astrocytes. The induction of RANTES mRNA in microglia by IFNβ, IL-1β or TNFα was variable, showing no to low level expression depending on the case, whereas LPS provided a consistent inducing signal. In astrocytes, only cytokine combinations (IFN ± IL-1β) effectively induced the RANTES mRNA. These results demonstrate that distinct sets of chemokine genes are induced in human glial cells by cytokines and interferons. These results may have wide implications for inflammatory, vascular and neoplastic diseases of the CNS. (C) 2000 Wiley-Liss, Inc.