Human parvovirus B19 (B19) DNA was detected in the synovial tissues in 30 of 39 patients with rheumatoid arthritis (RA), and infrequently in those with osteoarthritis and traumatic joints. On the other hand, the expression of the B19 antigen VP-1 was specific (

Adenoma malignum of the uterine cervix (mucinous type of minimal deviation adenocarcinoma, mucinous MDA), is a unique neoplasm that is difficult to diagnose owing to the deceptively benign appearance of the tumour cells. The present study was undertaken to explore the phenotypic expression of this tumour compared with those of non-neoplastic cervical tissues and of cervical carcinomas of various types. Ten cases of mucinous MDA, 50 cases with non-neoplastic cervical tissues, 13 of cervical adenocarcinoma including the mucinous (endocervical or intestinal type) and endometrioid types, and 2 of mucoepidermoid carcinoma were examined by various histochemical staining methods, including those for gastric mucins, pepsinogen, lysozyme, chromogranin A and carcinoembryonic antigen. The results revealed that mucinous MDA characteristically exhibited gastric phenotypes. The presence of gastric metaplasia was also demonstrated in 9 cases of mucinous MDA and in 5 of the other cases examined. The 7 endocervical-type adenocarcinomas also included 4 that expressed gastric phenotypes, and 2 of the 3 intestinal-type adenocarcinomas showed the same properties focally. These results indicate the presence of a group of lesions expressing gastric phenotypes in the uterine cervix and suggest a close relationship between these lesions. Cervical adenocarcinomas expressing gastric phenotypes are probably derived from MDA.

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The innate immune system of humans recognizes the human pathogenic fungus Candida albicans via sugar polymers present in the cell wall, such as mannan and ␤-glucan. Here, we examined whether nucleic acids from C. albicans activate dendritic cells. C. albicans DNA induced interleukin-12p40 (IL-12p40) production and CD40 expression by murine bone marrow-derived myeloid dendritic cells (BM-DCs) in a dose-dependent manner. BM-DCs that lacked Toll-like receptor 4 (TLR4), TLR2, and dectin-1, which are pattern recognition receptors for fungal cell wall components, produced IL-12p40 at levels comparable to the levels produced by BM-DCs from wild-type mice, and DNA from a C. albicans pmr1⌬ null mutant, which has a gross defect in mannosylation, retained the ability to activate BM-DCs. This stimulatory effect disappeared completely after DNase treatment. In contrast, RNase treatment increased production of the cytokine. A similar reduction in cytokine production was observed when BM-DCs from TLR9 ؊/؊ and MyD88 ؊/؊ mice were used. In a luciferase reporter assay, NF-B activation was detected in TLR9-expressing HEK293T cells stimulated with C. albicans DNA. Confocal microscopic analysis showed similar localization of C. albicans DNA and CpG-oligodeoxynucleotide (CpG-ODN) in BM-DCs. Treatment of C. albicans DNA with methylase did not affect its ability to induce IL-12p40 synthesis, whereas the same treatment completely eliminated the ability of CpG-ODN to induce IL-12p40 synthesis. Finally, impaired clearance of this fungal pathogen was not found in the kidneys of TLR9 ؊/؊ mice. These results suggested that C. albicans DNA activated BM-DCs through a TLR9-mediated signaling pathway using a mechanism independent of the unmethylated CpG motif.

Human parvovirus B19 frequently causes acute and chronic arthritis in adults. The molecular mechanism of B19 arthritis, however, remains poorly understood. We previously showed that the transmission of B19 from rheumatoid synoviocytes to monocytic cells is associated with enhanced secretion of tumor necrosis factor alpha (TNF-␣), which triggers inflammation, and interleukin-6. To determine the role of B19 in the production of TNF-␣, we focused on the function of its nonstructural protein, NS1, and established monocytic U937 lines transduced with the NS1 gene under the control of an inducible promoter. Production of TNF-␣ mRNA and protein was elevated in a manner associated with NS1 expression. Reporter assays revealed that AP-1 and AP-2 motifs on the TNF-␣ promoter were responsible for NS1-mediated up-regulation. Electrophoretic mobility shift assay showed specific binding of nuclear proteins from NS1 gene-transduced cells with the AP-1 or AP-2 probe. Antibodies against transcription factors AP-1 and AP-2 and anti-NS1 antibody inhibited the binding of nuclear proteins to the corresponding probes. These data indicate that NS1 up-regulates TNF-␣ transcription via activation of AP-1 and AP-2 in monocytic cells. The molecular mechanisms of NS1-mediated TNF-␣ expression would explain the pathogenesis of B19-associated inflammation.Human parvovirus B19 belongs to the family Parvoviridae and the genus Erythrovirus. The B19 genome includes three major open reading frames coding for the nonstructural protein NS1 in the left half and structural proteins VP1 and VP2 in the right half (44). B19 is the only parvovirus that has been clearly linked with disease in humans. Common manifestations caused by B19 infection include transient aplastic crisis in patients with histories of chronic hemolytic anemia (37), erythema infectiosum (7), nonimmune hydrops fetalis (9), chronic pure red cell aplasia in patients with immunosuppression (24), and arthralgia or arthropathy (59). Acute onset of polyarthritis is common in adults (mostly women) (60). Joint symptoms last for 1 to 3 weeks, although they may persist for months or years. B19 arthritis often meets clinical diagnostic criteria for rheumatoid arthritis and can be erosive (12,19,35,53,59). Because it has been observed that joint symptoms caused by B19 infection coincide with the appearance of specific immunoglobulin G (IgG) and the disappearance of viremia (2) and joint symptoms occur in chronically infected subjects after treatment with immunoglobulin (17), immune complex is thought to cause acute polyarthropathy. However, molecular mechanisms for the involvement of immune complexes in joint inflammation are unclear.Tumor necrosis factor alpha (TNF-␣), a representative proinflammatory cytokine, is an important mediator in the inflammatory process associated with many types of infections and autoimmune diseases through induction of a variety of cytokines, chemokines, and proteases in autocrine and paracrine pathways (16,55). Although various cell types are capable of producing T...

Low-energy extracorporeal shock wave (LE-ESW) treatment has been shown to accelerate wound repair; however, the mechanisms of treatment remain unclear. In the present study, we addressed the role of endothelial nitric oxide synthase (eNOS). A single LE-ESW treatment accelerated the healing of wounds in diabetic mice caused by the injection of streptozotocin. This accelerated healing was accompanied by the increased expression of eNOS and vascular endothelial growth factor (VEGF) and the generation of new vessels at the wound tissues. These results raised the possibility that eNOS may be involved in the beneficial effects of LE-ESW treatment. To address this possibility, we compared the effects of this treatment between mice with a genetic disruption of eNOS knockout (eNOS-KO mice) and wild-type (WT) control mice. Interestingly, the LE-ESW-induced acceleration of wound closure and the increase in VEGF expression and neovascularization was significantly attenuated in eNOS-KO mice compared with WT mice. Considered collectively, these results showed that eNOS was induced at the wound tissues by LE-ESW treatment and played a critical role in the therapeutic effects of this treatment by accelerating the wound healing by promoting VEGF expression and neovascularization.

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Wound healing is promoted by the presence of replicating microorganisms adhering to the wounded tissue, but the precise mechanism is not fully understood. In the present study, using a rat model with full-thickness dermal wounds, we examined the effect of Pseudomonas aeruginosa inoculation on wound healing and the role of neutrophils infiltrating the wound site. Within 3 days, inoculation with this bacterium had accelerated re-epithelialization, epidermal cell proliferation, and neo-vascularization, as well as the local infiltration of neutrophils, which reached a peak at 24 hours. Tumor necrosis factor (TNF)-α was detected in the wound tissues on the mRNA and protein levels within 24 hours. Flow cytometry and immunohistochemical analyses detected higher levels of TNF-α in the infiltrating neutrophils in rats inoculated with P. aeruginosa than in uninoculated rats. Neutropenic rats treated with anti-neutrophil mAb or cyclophosphamide exhibited significant attenuation in re-epithelialization, epidermal cell proliferation, neo-vascularization, and TNF-α synthesis compared with control; administration of TNF-α reversed these attenuations. These wound-healing responses were decelerated in rats treated with anti-TNF-α mAb, as was the infiltration of neutrophils. These results indicate that inoculation with P. aeruginosa promotes wound healing by inducing the infiltration of neutrophils, which play a critical role as a major source of TNF-α.