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B Pathway1
*
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada;
Departments of Microbiology and Internal Medicine, University of Iowa and the Veterans Affairs Medical Center, Iowa City, IA 52242; and
Department of Microbiology, Washington State University, Pullman, WA 99164
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-
B. Inhibiting the activation of
NF-B, either by treating cells with a chemical inhibitor,
BAY11-7082, or by inducibly expressing a superrepressor form of
IB
, 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.
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