Abstract:
The alternative (noncanonical) nuclear factor-κB (NF-κB) signaling pathway predominantly regulates the function of the p52/RelB heterodimer.
Germline Nfkb2 deficiency in mice leads to loss of p100/p52 protein and offers protection against a variety of gastrointestinal
conditions, including azoxymethane/dextran sulfate sodium (DSS)-induced colitis-associated cancer and lipopolysaccharide (LPS)-
induced small intestinal epithelial apoptosis. However, the common underlying protective mechanisms have not yet been fully elucidated.
We applied high-throughput RNA-Seq and proteomic analyses to characterize the transcriptional and protein signatures of the
small intestinal mucosa of naïve adult Nfkb2 / mice. Those data were validated by immunohistochemistry and quantitative ELISA
using both small intestinal tissue lysates and serum. We identified a B-lymphocyte defect as a major transcriptional signature in the
small intestinal mucosa and immunoglobulin A as the most downregulated protein by proteomic analysis in Nfkb2 / mice. Small intestinal
immunoglobulins were dramatically dysregulated, with undetectable levels of immunoglobulin A and greatly increased
amounts of immunoglobulin M being detected. The numbers of IgA-producing, cluster of differentiation (CD)138-positive plasma cells
were also reduced in the lamina propria of the small intestinal villi of Nfkb2 / mice. This phenotype was even more striking in the
small intestinal mucosa of RelB / mice, although these mice were equally sensitive to LPS-induced intestinal apoptosis as their
RelBþ/þ wild-type counterparts. NF-κB2/p52 deficiency confers resistance to LPS-induced small intestinal apoptosis and also appears
to regulate the plasma cell population and immunoglobulin levels within the gut.
