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 aggressive periodontitis have significantly elevated levels of plasma C-reactive protein and interleukin-6. These elevated inflammatory factors might potentially increase the risk for cardiovascular events and glucose dysregulation in relatively young individuals.

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.

Background and Objective:  Vitamin D‐binding protein (DBP) is a multifunctional and highly expressed plasma protein. Among its diverse roles, including those in the immune and inflammatory responses, it is the primary carrier of vitamin D, which has been implicated in periodontitis. We hypothesized that there is a correlation between systemic DBP levels and generalized aggressive periodontitis (GAgP). Material and Methods:  Forty‐four patients with GAgP and 32 healthy controls were recruited. Clinical parameters were examined, including the mean bleeding index, probing depth, attachment loss and percentage of severely affected sites. Blood chemistry analyses were performed for each subject. Plasma levels of DBP, interleukin‐6 (IL‐6) and procalcitonin (PCT) were measured using ELISAs, and plasma levels of 25‐hydroxy‐vitamin D3 (25(OH)D3) were detected using a radioimmunoassay. Results:  Significantly higher levels of plasma DBP, IL‐6, PCT and 25(OH)D3, as well as leukocyte counts, neutrophil counts and neutrophil percentages were found in patients with GAgP compared with healthy controls (p < 0.05 for all). Multiple linear regression analysis showed that the plasma DBP levels were significantly correlated with GAgP, plasma PCT levels and smoking status (p < 0.05 for all). In the GAgP group, the plasma DBP levels in smokers were significantly higher than those in nonsmokers (p < 0.001). Conclusion:  Elevated plasma vitamin DBP levels are associated with GAgP.

These findings indicate that aggressive periodontitis is associated with elevated levels of plasma calprotectin and that gene polymorphisms of S100A8 may influence the susceptibility and severity of aggressive periodontitis.

Background: TNFR1 signaling has been intensively studied, but it remains unclear how TNFR2 transduces TNF-␣ signal under inflammatory conditions. Results: TNFR2 associates with IL-17RD, resulting in receptor aggregation and TRAF2 recruitment, leading to promotion of NF-B signaling in renal tubular epithelial cells. Conclusion: TNFR2 cooperates with IL-17RD to activate NF-B. Significance: The TNFR2⅐IL-17RD heteromer might be implicated in nephritis.