Background Mast cell (MC) progenitors leave the bone marrow, enter the circulation, and settle in the skin and other tissues. Their maturation in tissues is influenced by the surrounding microenvironment. Objective We tested the hypothesis that environmental factors play a role in MC maturation in the skin. Methods MCs were numerically, phenotypically, and functionally compared between germ-free (GF), SPF, and GF mice reconstituted with microbiota. Maturity of MCs was then correlated with skin levels of stem cell factor (SCF), a critical MC differentiation factor, and lipoteichoic acid (LTA), a TLR2 ligand. MCs were also evaluated in mice with keratinocyte-specific deletion of Scf. Results We found that GF mice express abnormally low amounts of stem cell factor (SCF), a critical MC differentiation factor, and contain MCs that are largely undifferentiated. Reconstituting the GF microbiota reverted this MC phenotype to normal, indicating that the phenotype is related to ongoing interactions of microbiota and skin. Consistent with the immaturity of GF MCs, degranulation-provoking compound 48/80 induced less edema in the skin of GF mice than in conventional mice. Our results show that the skin microbiome drives SCF production in keratinocytes, which triggers the differentiation of dermal MCs. Since the skin microbiome is a rich source of lipoteichoic acid (LTA), a TLR2 ligand, we mimicked the GF microbiome impact on MCs by applying LTA to the skin of GF mice. We also demonstrated that MC migration within the skin depends exclusively on keratinocyte-produced SCF. Conclusion This study has revealed a novel mechanism by which the skin microbiota signals the recruitment and maturation of MCs within the dermis via SCF production by LTA-stimulated keratinocytes.

Most targeted anticancer drugs are inhibitors of kinases that are aberrantly activated in cancer cells. However, the mechanisms by which kinase inhibitors suppress tumor growth remain unclear. In this study, we found that UCN-01, a staurosporine analogue and broad-range kinase inhibitor used in clinical trials, inhibits colon cancer cell growth by inducing apoptosis via PUMA, a BH3-only Bcl-2 family member and a p53 target. PUMA expression was markedly elevated in a p53-independent fashion following UCN-01 treatment. The induction of PUMA by UCN-01 was mediated by direct binding of FoxO3a to the PUMA promoter following inhibition of AKT signaling. Deficiency in PUMA abrogated UCN-01-induced apoptosis, caspase activation, and mitochondrial dysfunction, and rendered UCN-01 resistance in a clonogenic assay, whereas elevated PUMA expression or a BH3 mimetic sensitized UCN-01 induced apoptosis. Chemosensitization by UCN-01 seemed to involve simultaneous PUMA induction through both p53-dependent and p53-independent mechanisms. Furthermore, deficiency in PUMA suppressed the antitumor effects of UCN-01 in a xenograft model, concurrent with reduced apoptosis and caspase activation in vivo. These results suggest that PUMA-mediated apoptosis is pivotal for the anticancer activities of UCN-01, and possibly other clinically used kinase inhibitor drugs, and that PUMA manipulation may be useful for improving their anticancer activities. Mol Cancer Ther; 9(11); 2893-902. ©2010 AACR.

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Patients with AgP may have elevated peripheral leukocyte numbers and serum globulin levels as well as decreased serum albumin levels and albumin/globulin ratios compared to controls. These changes might be associated with the severity of periodontal destruction.