Regulation of human IP-10 gene expression in astrocytoma cells by inflammatory cytokines

Majumder S., Zhou L. Z., Chaturvedi P., Babcock G., Aras S., Ransohoff R. M.

Journal of Neuroscience Research, cilt.54, sa.2, ss.169-180, 1998 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 54 Sayı: 2
  • Basım Tarihi: 1998
  • Dergi Adı: Journal of Neuroscience Research
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.169-180
  • Anahtar Kelimeler: Astrocytes, Chemokines, Gene transcription, Interferons, TNF
  • Ankara Üniversitesi Adresli: Hayır

Özet

Because of its prominent expression in central nervous system inflammatory pathology by astrocytes, we examined the mechanism of human IP- 10 (hIP-10) gene induction by interferon-γ (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in astrocytoma cells. When present together, IFN-γ and TNF-α induced robust accumulation of hIP-10 mRNA, but hIP-10 mRNA was minimally induced when astrocytoma cells were treated with individual cytokines. This pattern of expression resembled that previously described for murine IP-10 (mIP-10) gene induction in fibroblasts and in rat astroglia. Nuclear run-on experiments showed that the synergistic effect of the cytokines resulted from an increased rate of IP-10 transcriptional initiation. Functional analysis of the hIP-10 promoter after deletion and substitution mutagenesis indicated that an interferon-stimulated response element (ISRE) governed both simple response to IFN-γ and synergy with TNF- α. Synergistic induction of hIP-10 also required an ISRE-proximal nuclear factor kappa-B (NFκB) binding site. TNF-α-induced NFκB binding activity at this site was composed of RelA (p65) homodimers. Our results document that cis-elements through which cytokines mediate synergistic induction of IP-10 in mouse and human are strictly conserved despite divergence elsewhere within the proximal 5'-flanking region.