Soluble epoxide hydrolase inhibitor promotes immunomodulation to inhibit bone resorption.

BACKGROUND AND OBJECTIVE: Soluble epoxide hydrolase (sEH) is an enzyme in the arachidonate cascade which converts epoxy fatty acids (EpFAs), such as epoxyeicosatrienoic acids (EETs) produced by cytochrome P450 enzymes, to dihydroxy-eicosatrienoic acids. In the last 20 years with the development of inhibitors to sEH it has been possible to increase the levels of EETs and other EpFAs in in vivo models. Recently, studies have shown that EETs play a key role in blocking inflammation in a bone resorption process, but the mechanism is not clear. In the current study we used the sEH inhibitor (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea [TPPU]) to investigate the immunomodulatory effects in a mouse periodontitis model. MATERIAL AND METHODS: Mice were infected on days 0, 2, and 4 with Aggregatibacter actinomycetemcomitans and divided into groups (n = 6) that were treated orally, daily for 15 days, with 1 mg/kg of TPPU. Then, the mice were killed and their jaws were analyzed for bone resorption using morphometry. Immunoinflammatory markers in the gingival tissue were analyzed by microarray PCR or western blotting. RESULTS: Infected mice treated with TPPU showed lower bone resorption than infected mice without treatment. Interestingly, infected mice showed increased expression of sEH; however, mice treated with TPPU had a reduction in expression of sEH. Besides, several proinflammatory cytokines and molecular markers were downregulated in the gingival tissue in the group treated with 1 mg/kg of TPPU. CONCLUSION: The sEH inhibitor, TPPU, showed immunomodulatory effects, decreasing bone resorption and inflammatory responses in a bone resorption mouse model.

Possible involvement of IL-21 and IL-10 on salivary IgA levels in chronic periodontitis subjects.

Specific cytokines and the costimulatory protein CD40 play role in inducing immunoglobulin (Ig)A production by B cells in the humoral immune response. However, to date, the role of these mediators was not investigated in chronic periodontitis. Therefore, the aim of this study was to assess the local levels of interleukin (IL)-21, IL-21 receptor (IL-21R), IL-4, IL-10 and CD40 ligand (CD40L) on chronic periodontitis subjects and their relationship with the salivary levels of IgA. Gingival biopsies and un-stimulated saliva were collected from chronic periodontitis (n = 15) and periodontally healthy (n = 15) subjects. The mRNA levels of IL-4, IL-10, IL-21, IL-21R, CD40L in the gingival biopsies were evaluated by quantitative real-time polymerase chain reaction. The salivary levels of IgA and the levels of IL-4 and IL-10 in the gingival biopsies were analyzed by ELISA. The mean levels of IgA were significantly higher in the chronic periodontitis compared to periodontally healthy group (P < 0.05). The mRNA levels for IL-21 was higher (P < 0.05) in the chronic periodontitis when compared to the healthy group. However, the expression of IL-21R and CD40L did not differ between groups. The IL-10 was significantly elevated at mRNA and protein levels in chronic periodontitis when compared to periodontally healthy group (P < 0.05). Conversely, the mRNA levels as well as the protein amount of IL-4 were significantly lower (P < 0.05) in chronic periodontitis than healthy ones. In conclusion, the upregulation of IL-21 and IL-10 and downregulation of IL-4 in periodontitis tissues may be collectively involved in the increased levels of salivary IgA in chronic periodontitis subjects.

Angiogenesis in salivary carcinomas with and without myoepithelial differentiation.

To investigate whether salivary carcinomas with and without myoepithelial differentiation could present differences regarding degree of angiogenesis, we compared tumor vascularization between adenoid cystic (31 cases) and epithelial-myoepithelial carcinomas (14) versus mucoepidermoid (37) carcinoma. The expression of peroxiredoxin I was also studied to verify the potential relationship between cellular metabolism and microvascular density. Microvascular density for CD34 and CD105 were significantly lower in carcinomas with myoepithelial differentiation. However, no correlation was found between degree of angiogenesis and amounts of myoepithelial cells. High-grade peroxiredoxin I expression was found in 73.7% of mucoepidermoid carcinomas, whereas 85.1% of carcinomas with myoepithelial differentiation presented low-grade expression. In conclusion, carcinomas with myoepithelial differentiation, regardless of the amounts of myoepithelial cells, are associated to a significantly lower vascular density. The reasons for this lower angiogenic activity remain to be determined but could be related to metabolic characteristics of the cancer cells.

Peroxiredoxin I is differentially expressed in multiple myelomas and in plasmablastic lymphomas.

BACKGROUND: Plasmablastic lymphoma (PBL) and multiple myeloma (MM) are B cell-derived malignancies that share many morphologic and immunophenotypic traits, making the differential diagnosis particularly complicated. We have recently demonstrated that peroxiredoxin I (PrdxI) is expressed in plasma cells but not in B lymphocytes, suggesting that its expression is development-associated. AIM: To analyze PrdxI expression in PBL and in MM in order to study its utilization as an additional diagnostic molecular tool. METHODS AND RESULTS: Eight cases of PBL and nine of MM were studied by immunohistochemistry. We have demonstrated that PrdxI expression is closely connected with the immunoglobulin production capacity of the cells, which means high in MM, but absent in PBL cases, except one, wherein few cells were stained. CONCLUSIONS: We hypothesize PrdxI as a component of the unfolded protein response (UPR), an adaptive pathway essential for plasma cell differentiation. As we have not detected immunoglobulin in our PBL cases, we suggest that UPR was not activated in the cells, accounting for the impediment of the developmental process, and for the inhibition of PrdxI expression observed. PrdxI could be considered an additional plasma cell functional marker and could also be speculated as a therapeutic target in the treatment of MM.