Abstract
Abstract The tumor suppressor p53, a crucial gene in controlling cell cycle and apoptosis, is inactivated via somatic mutations in inflamed tissues, such as synovial fibroblasts of rheumatoid arthritis and cancer infiltrating fibroblasts. Recent studies by our laboratory and others suggest that p53 inactivation in immune cells promotes a pro-inflammatory host microenvironment - elevated serum inflammatory cytokines/chemokines, and enhanced Th17 cells, and augmented differentiation of myeloid cells, including myeloid derived suppressors (MDSCs). Recently, compelling evidence suggests that stroma of the secondary lymphoid organs (SLO) also plays a vital role in immune regulation. We, thus, examined the potential immunomodulatory function of p53null stroma for host immune microenvironment. While the frequency of CD45- stroma in the SP and BM of p53null mice did not differ from that of WT mice, p53null, but not WT, stroma was readily expanded in culture, as well as in the spleen of B16F1tumor bearing p53nullmice. The stromal cells were CD106hiCD54+GP38+Sca-1lo/- fibroblastic reticular cell (FRC)-like that expressed high levels of proinflammatory cytokine/chemokine and immunosuppressive mediators. They enhanced the survival and differentiation of MDSCs and likely regulate the function of other immune cells. Together, our results suggest that p53null stroma is highly immunosuppressive, which modulates host immune-microenvironment via cytokine/chemokine and stroma-immune cell interaction.
Published Version
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