TY - JOUR
T1 - Melphalan-induced up-regulation of B7-1 surface expression on normal splenic B cells
AU - Donepudi, Manjula
AU - Jovasevic, Vladimir M.
AU - Raychaudhuri, Pradip
AU - Mokyr, Margalit B.
N1 - Funding Information:
Acknowledgements This work was supported by Research Grant R01 CA-76532 from the National Institutes of Health. M.D. participated in this study in partial fulfillment of the requirements for the Doctor of Philosophy degree.
PY - 2003/3/1
Y1 - 2003/3/1
N2 - 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.
AB - 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.
KW - B cell
KW - Costimulatory molecule
KW - Gene regulation
KW - Melphalan-induced gene expression
UR - http://www.scopus.com/inward/record.url?scp=0037382989&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037382989&partnerID=8YFLogxK
U2 - 10.1007/s00262-002-0345-8
DO - 10.1007/s00262-002-0345-8
M3 - Article
C2 - 12649745
AN - SCOPUS:0037382989
SN - 0340-7004
VL - 52
SP - 162
EP - 170
JO - Cancer Immunology and Immunotherapy
JF - Cancer Immunology and Immunotherapy
IS - 3
ER -
