Convergence of CpG DNA- and BCR-mediated signals at the c-Jun N-terminal kinase and NF-kappaB activation pathways: regulation by mitogen-activated protein kinases

Abstract

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-kappaB, 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-kappaB 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.

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division

“…Besides the level of Akt activation, the constitutive nuclear translocation of transcription factors has been proposed as hallmark of the disease stage in CLL patients. 6,24,25 Indeed, in our study, we confirmed that constitutive activation of both Akt and NF-kB is detectable mainly in B cells from HR CLL patients. Noteworthy, we found that LAIR-1 is differently expressed on HR and LR CLL, being absent on most HR CLL: this may provide an explanation for the lack of control of kinase activation, in particular Akt, mostly found in HR CLL.…”

“…Indeed, p38, JNK and Akt converge to the LAIR-1-mediated inhibition of B-cell proliferation A Poggi et al activation of transcription factors, such as NF-kB, which may lead to cell survival and proliferation. 5,6,24,34,35 We have previously reported that LAIR-1 can inhibit proliferation of acute myeloid leukaemia blasts induced by growth factors, by preventing NF-kB nuclear translocation, and this effect is ITIMdependent. 17,18 Along this line, we observed that LAIR-1 engagement blocks both constitutive and sIgM-induced NF-kB activation in CLL.…”

“…6,24,34 In our experiments, Akt phosphorylation was measured on lysates of B lymphocytes from CLL patients (n ¼ 8 HR, n ¼ 9 IR, n ¼ 8 LR) compared with B lymphocytes from healthy donors (n ¼ 10). As shown in Figure 5a, Akt is constitutively phosphorylated in all HR CLL; a lower, but significant Akt activation was observed in IR CLL, compared with LR CLL and healthy controls ( Figure 5a).…”

“…[20][21][22][23] In turn, a link between p38 MAPK, JNK or ERK activation and NF-kB nuclear translocation has been described in a murine B lymphoma cell line. 24 In this paper, we show that: (i) LAIR-1 is mostly absent in highrisk (HR) CLL and differentially expressed in intermediate-risk (IR) and low-risk (LR) CLL and the intensity of expression relates to the stage of disease: (ii) constitutive and BCR-mediated activation of p38 and JNK is inhibited by LAIR-1 through an ITIM-dependent signal that is missing in HR CLL; (iii) when the molecule is expressed, engagement of LAIR-1 blocks Akt and NF-kB activation and prevents CLL division.…”

The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease

“…[33][34][35][36] Although a role for JNK in B-cell proliferation has also been established, it is still not known whether quantitative differences in JNK activation can influence cell cycle progression. [37][38][39] We therefore decided to further investigate the possibility that the stronger proliferative response of progressive/V H unmutated CLL B-cells is due to increased signaling through the Akt or ERK pathway. To enforce activation of these kinases, we transfected primary CLL B-cells that were nonresponsive to CpG ODN-induced proliferation with constitutively active MEK2 and myristoylated Akt constructs.…”