CpG DNA rescues B cells from apoptosis by activating NFkappaB and preventing mitochondrial membrane potential disruption via a chloroquine-sensitive pathway.
Isolated murine splenic B cells gradually undergo spontaneous apoptosis while WEHI-231 B lymphoma cells undergo activation-induced apoptosis. Unmethylated CpG dinucleotides in a particular sequence context (CpG motif) in bacterial DNA or in synthetic oligodeoxynucleotides (CpG DNA) rescue both splenic B cells and WEHI-231 cells from apoptosis, an effect which could potentially contribute to autoimmune disease. Chloroquine has been used as an effective therapeutic agent for some autoimmune diseases, although the mechanism of action is not clearly understood. Low concentrations of chloroquine (<5 microM) selectively abolished CpG DNA-mediated protection against spontaneous apoptosis of splenic B cells and against anti-IgM-induced apoptosis of WEHI-231 cells without affecting anti-apoptotic activities of anti-CD40 or lipopolsaccharide. CpG DNA effectively prevented mitochondrial membrane potential disruption through a chloroquine-sensitive pathway in splenic B cells. Apoptosis protection by CpG DNA was also associated with increased expression of several proto-oncogenes and oncoproteins directly and/or indirectly through a rapid and sustained activation of NFkappaB in splenic B cells and WEHI-231 cells. These effects were also suppressed by chloroquine. Our results suggest that despite the difference in maturation phenotype of splenic B cells and WEHI-231 cells, CpG DNA rescues both from apoptosis by similar pathway, which is blocked at an early step by chloroquine.
Yi
A K
AK
Interdisciplinary Graduate Program in Immunology, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Peckham
D W
DW
Ashman
R F
RF
Krieg
A M
AM
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000502:physiology*; D002738:Chloroquine / Q000494:pharmacology*; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011519:Proto-Oncogenes; D051020:bcl-X Protein
D000888:Antibodies, Anti-Idiotypic; D002738:Chloroquine; D015226:Dinucleoside Phosphates; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C494812:Bcl2l1 protein, mouse; C044203:anti-IgM; C015772:CpG dinucleotide