CD40 Signaling in B Cells Regulates the Expression of the Pim-1 Kinase Via the NF-κB Pathway

Abstract

The ability of CD40 signaling to regulate B cell growth, survival, differentiation, and Ig class switching involves many changes in gene expression. Using cDNA expression arrays and Northern blotting, we found that CD40 signaling increased the mRNA levels for pim-1, a protooncogene that encodes a serine/threonine protein kinase. Subsequent experiments showed that CD40 engagement also increased both Pim-1 protein levels and Pim-1 kinase activity in B cells. We then investigated the signaling pathways by which CD40 regulates Pim-1 expression and found that CD40 up-regulates Pim-1 primarily via the activation of NF-κB. Inhibiting the activation of NF-κB, either by treating cells with a chemical inhibitor, BAY11-7082, or by inducibly expressing a superrepressor form of IκBα, significantly impaired the ability of CD40 to increase Pim-1 protein levels. Because Pim-1 expression is associated with cell proliferation and survival, we asked whether this correlated with the ability of CD40 signaling to prevent anti-IgM-induced growth arrest in the WEHI-231 murine B cell line, a model for Ag-induced clonal deletion. We found that the anti-IgM-induced growth arrest in WEHI-231 cells correlated with a substantial decrease in Pim-1 levels. In contrast, culturing WEHI-231 cells with either anti-CD40 Abs or with the B cell mitogen LPS, both of which prevent the anti-IgM-induced growth arrest, also prevented the rapid decline in Pim-1 levels. This suggests that Pim-1 could regulate the survival and proliferation of B cells.

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

“…5C). This finding agrees with other studies showing that NFκB signaling regulates Pim-1 expression in B cells (46). Overall, these data show that NFκB and Pim-1 regulate each other in CD8 T cells and may function to preserve a continuum of NFκB signaling when antigenic/ inflammatory signals are low or not present.…”

Gain of chromosome 6p is an infrequent cause of increased PIM1 expression in B-cell non-Hodgkin's lymphomas

“…It has been shown that the NF-kappa B pathway is involved in PIM1 regulation. 5 This would fit well with the fact that high PIM1 expression mainly is found in activated B-cell like DLBCL (ABC), which are characterized by constitutive activation of the NF-kappa B pathway. 4 Recently, it was shown that that inhibitors of IkappaB kinase (IKK) are toxic for ABC DLBCL cell lines, but not for cell lines derived from the germinal center like DLBCLs.…”

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

“…U0126 (New England Biolab) is a potent and specific inhibitor of MEK-1/2, and SB202190 (Calbiochem, La Jolla, CA) is a specific inhibitor of p38. Bay11-7082 and Bay11-7085 (both from Calbiochem) are specific inhibitors of I B phosphorylation (30)(31)(32). U0124 and SB202474 (both from Calbiochem) are control compounds for U0126 and SB202190, and these do not inhibit MEK-1/2 and p38 enzymatic activity, respectively.…”