International Immunology, Vol. 15, No. 5, pp. 577-591,
May 2003
© 2003 Japanese Society for Immunology
Convergence of CpG DNA- and BCR-mediated signals at the c-Jun N-terminal kinase and NF-
B activation pathways: regulation by mitogen-activated protein kinases
1 Children’s Foundation Research Center at Le Bonheur Children’s Medical Center and Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA 2 Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA 3 Interdisciplinary Graduate Program in Immunology and Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242, USA 4 Department of Veteran Affairs Medical Center, Iowa City, IA 52246, USA 5 Coley Pharmaceutical Group Inc., Wellesley, MA 02481, USA
Correspondence to: A.-K. Yi; E-mail: ayi{at}utmem.edu
Transmitting editor: Kenneth Murphy
Depending on the experimental model, unmethylated CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (CpG DNA) either augment or antagonize BCR-induced signals in B cells. CpG DNA synergizes with BCR-induced proliferation and Ig production of mature B cells, but blocks BCR-mediated apoptosis of immature B cells. Here, we demonstrate using a murine B lymphoma cell line WEHI-231, which is a model for immature B lymphocytes, that CpG DNA augments BCR-mediated signals for the activation of mitogen-activated protein kinase (MAPK) kinase (MKK)3, MKK4 and MKK6, and their subsequent downstream effectors c-Jun N-terminal kinase (JNK) and p38, but does not enhance MEK1/2 or extracellular signal-regulated kinase (ERK) activation. CpG DNA- and BCR-mediated signals also synergize for the activation of transcription factors AP-1, NFAT and NF-
B, but not for cAMP-responsive elements binding factor. Synergistic activations of JNK and p38 contribute to the synergistic production of cytokines induced by CpG DNA- and BCR-mediated signals, but have little or no effect on the ability of CpG DNA to protect WEHI-231 cells from anti-IgM-induced growth arrest. In contrast, all three MAPK, JNK, ERK and p38, contribute to the synergistic induction of splenic mature B cell proliferation by CpG DNA and anti-IgM. These results indicate that CpG DNA- and BCR-mediated signals converge at the level of MKK, NF-B and NFAT activation, and that MAPK have differential regulatory roles for CpG DNA-mediated cytokine production versus cell proliferation in splenic mature B cells and WEHI-231 cells.
Keywords: apoptosis, B Lymphocyte, BCR, CpG DNA, cytokine, protein kinase
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