Melphalan-induced up-regulation of B7-1 surface expression on normal splenic B cells

Manjula Donepudi, Vladimir M. Jovasevic, Pradip Raychaudhuri, Margalit B. Mokyr

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

We have previously shown that exposure of MOPC-315 or P815 tumor cells to the widely used anticancer drug melphalan (L-PAM, L-phenylalanine mustard) leads to rapid up-regulation of B7-1 surface expression. Since B7 - 1-expressing tumor cells depend on B7-expressing host antigen presenting cells (APC) for the generation of CD8+ T-cell-mediated antitumor immunity, and since L-PAM promotes the acquisition of tumor-eradicating immunity by CD8+ T-cells from MOPC-315 tumor bearers, the current studies were undertaken to determine if L-PAM also up-regulates B7-1 expression on host APC. Here we show that exposure of normal spleen cells to L-PAM leads within 24 h to up-regulated B7-1 expression on B220+ cells (B cells). Studies into the mechanism through which L-PAM leads to up-regulated B7-1 expression revealed that within 2 h after exposure of normal spleen cells to L-PAM, accumulation of B7-1 mRNA is evident and this accumulation requires de novo RNA synthesis, indicating that the regulation is at the transcriptional level. The L-PAM-induced accumulation of B7-1 mRNA was prevented with the antioxidant N-acetyl-L-cysteine (NAC), indicating that reactive oxygen species are important for the transcriptional regulation. Although AP-1 and NF-κB are considered redox-sensitive transcription factors, L-PAM led only to activation of NF-κB that bound specifically to a probe containing the corresponding binding site in the B7-1 gene. Moreover, selective inhibition of NF-κB activation prevented the L-PAM-induced B7-1 mRNA accumulation, indicating that NF-κB activation is essential for L-PAM-induced B7-1 gene expression in normal spleen cells. Finally, in vivo administration of an immunopotentiating dose of L-PAM to normal mice was found to up-regulate B7-1 mRNA expression in their spleens. Thus, the ability of L-PAM to up-regulate B7-1 expression not only on tumor cells but also on host cells may contribute to the potentiating activity of L-PAM for the acquisition of CD8+ T-cell-mediated tumor-eradicating immunity in tumor bearers.

Original languageEnglish (US)
Pages (from-to)162-170
Number of pages9
JournalCancer Immunology, Immunotherapy
Volume52
Issue number3
DOIs
StatePublished - Mar 1 2003

Keywords

  • B cell
  • Costimulatory molecule
  • Gene regulation
  • Melphalan-induced gene expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Immunology and Allergy
  • Immunology

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