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Biomedical subjects

Hiroo Yokozeki

Publications and source records attributed to Hiroo Yokozeki.

At least 19 recordsLinked to original sources
PubMed2006

The SYT-SSX fusion protein down-regulates the cell proliferation regulator COM1 in t(x;18) synovial sarcoma.

Chromosomal translocations are frequently associated with soft-tissue sarcomas. Fusion proteins generated by such translocations often play critical roles in tumorigenesis. Therefore, it is important to understand the function of the fusion protein to develop therapeutic interventions. The t(X;18)(p11.2;q11.2) translocation found in synovial sarcomas results in a fusion between the SYT gene on chromosome 18 and an SSX gene on the X chromosome. Although SYT-SSX fusion proteins appear to trigger synovial sarcoma development, little is known about the downstream targets of SYT-SSX. We found that the SYT-SSX fusion protein produces a dominant-negative function for SYT, which is a transcriptional coactivator. We then analyzed the gene expression profiles of SYT-SSX1-expressing HeLa cells using oligonucleotide microarrays and found that the SYT-SSX1 fusion protein directly down-regulated the expression of COM1, a regulator of cell proliferation. COM1 was found to be expressed at relatively low levels in synovial sarcoma tissues and cell lines. We then investigated the impact of conditional COM1 expression in the synovial sarcoma cell line. Increased COM1 expression resulted in induced apoptosis and in reduced cell growth and colony formation activity. Our results suggested that restoration of COM1 expression may be of therapeutic benefit in synovial sarcoma.

Apoptosis↗
PubMed2006

Fas- and FasL-deficient mice are resistant to the induction of bleomycin-induced scleroderma.

We have recently shown that apoptosis is induced in the lesional skin in a murine scleroderma model by local bleomycin injections, and the apoptotic pathway was mainly mediated by Fas/Fas ligand (FasL) signaling. To further investigate the involvement of apoptosis in scleroderma, we examined whether the induction of dermal sclerosis is suppressed in Fas-deficient (lpr) and FasL-deficient (gld) mice. Results of histological examination showed that the induction of dermal sclerosis by bleomycin treatment was significantly suppressed in both lpr and gld mice, in comparison with wild-type mice. The ratio of collagen contents in the bleomycin-treated skin as compared with PBS-treated skin was significantly lower in both lpr and gld mice than that in wild-type mice. The number of TUNEL-positive infiltrating cells was markedly increased following bleomycin exposure (60 +/- 11.4/HPF) in comparison with PBS treatment (9.5 +/- 6.0/HPF) in wild-type mice, which was significantly decreased in both lpr (22 +/- 4.5/HPF, P < 0.05) and gld (26 +/- 6.1/HPF, P < 0.05) mice. Our findings that lpr and gld mice were resistant to the induction of dermal sclerosis by bleomycin further suggest that Fas/FasL pathway is an important contributor involved in the pathophysiology of bleomycin-induced dermal sclerosis.

Animals↗
PubMed2006

Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor.

PGD(2) plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35-55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD(2)-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.

Animals↗
PubMed2006

Preventive effects of various types of footwear and cleaning methods on dermatophyte adhesion.

Tinea pedis is contagious and typically spreads from infected to non-infected persons. The purpose of this study was to evaluate the efficacy of footwear in preventing tinea pedis adhesion. Using the stamp culture method, we investigated the effectiveness of preventing dermatophyte passage by the wearing of stockings made of nylon, socks made of cotton and tabi (Japanese socks), as well as the effect of removing dermatophytes from these items by washing with soap, cold water and cold water after turning inside-out. For sandals, sneakers and boots, we also investigated the effect of dermatophyte removal by pouring cold water into the footwear, wiping with a wet towel, and pouring boiling water into the footwear. The wearing of socks or tabi was effective in preventing passage of dermatophytes. The stocking material proved to be too thin to prevent passage. On the inner side of socks (the side of the sole), all treatments were effective at removing dermatophytes, but on the outer side of socks (the side touching the surface of the sandals), the treatment of washing in cold water after turning inside-out resulted in significantly more dermatophytes as compared with the other treatments. Pouring cold water, wiping with a wet towel and pouring boiling water were all effective for removing dermatophytes from sandals and sneakers. However, for boots, the treatment of pouring cold water was less effective. To prevent the adhesion of dermatophytes to sandals, wearing socks or tabi was effective, and the treatments of washing socks in cold water after turning inside-out and of pouring cold water into the boots were less effective than the others.

Adult↗
PubMed2006

Reduction of human T-cell leukemia virus type 1 (HTLV-1) proviral loads in rats orally infected with HTLV-1 by reimmunization with HTLV-1-infected cells.

Human T-cell leukemia virus type 1 (HTLV-1) persistently infects humans, and the proviral loads that persist in vivo vary widely among individuals. Elevation in the proviral load is associated with serious HTLV-1-mediated diseases, such as adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. However, it remains controversial whether HTLV-1-specific T-cell immunity can control HTLV-1 in vivo. We previously reported that orally HTLV-1-infected rats showed insufficient HTLV-1-specific T-cell immunity that coincided with elevated levels of the HTLV-1 proviral load. In the present study, we found that individual HTLV-1 proviral loads established in low-responding hosts could be reduced by the restoration of HTLV-1-specific T-cell responses. Despite the T-cell unresponsiveness for HTLV-1 in orally infected rats, an allogeneic mixed lymphocyte reaction in the splenocytes and a contact hypersensitivity response in the skin of these rats were comparable with those of naive rats. HTLV-1-specific T-cell response in orally HTLV-1-infected rats could be restored by subcutaneous reimmunization with mitomycin C (MMC)-treated syngeneic HTLV-1-transformed cells. The reimmunized rats exhibited lower proviral loads than untreated orally infected rats. We also confirmed that the proviral loads in orally infected rats decreased after reimmunization in the same hosts. Similar T-cell immune conversion could be reproduced in orally HTLV-1-infected rats by subcutaneous inoculation with MMC-treated primary T cells from syngeneic orally HTLV-1-infected rats. The present results indicate that, although HTLV-1-specific T-cell unresponsiveness is an underlying risk factor for the propagation of HTLV-1-infected cells in vivo, the risk may potentially be reduced by reimmunization, for which autologous HTLV-1-infected cells are a candidate immunogen.

Administration, Oral↗
PubMed2006

Japanese cedar pollen as an exacerbation factor in atopic dermatitis: results of atopy patch testing and histological examination.

Atopy patch testing with Japanese cedar pollen extract has been used to investigate patients with atopic dermatitis whose condition is exacerbated by contact with Japanese cedar pollen. Comparative atopy patch testing, scratch tests, and assays for total IgE and specific IgE were performed in 74 patients with atopic dermatitis, 5 patients with Japanese cedar pollinosis and 15 control subjects. A skin biopsy was performed on any sites that were positive to Japanese cedar pollen patch test. The results after 48 h of atopy patch testing were compared with the patient's history, skin scratch test and specific IgE. Twenty-two of the 74 patients (30%) had a history of exacerbation every spring after contact with Japanese cedar. Of these patients 68% showed a positive reaction to Japanese cedar pollen extract, as did 21% of patients with atopic dermatitis without a history of exacerbation by Japanese cedar pollen, 20% of patients with Japanese cedar pollinosis without eruption and 7% of control subjects. A histological examination revealed eczematous changes and infiltration of lymphocytes and eosinophils in atopy patch testing positive sites. In conclusion, atopy patch testing with Japanese cedar pollen extract is a useful method for investigating trigger factors for eczematous skin lesions in a subgroup of patients with atopic dermatitis.

Adult↗
PubMed2006

STAT-6-mediated control of P-selectin by substance P and interleukin-4 in human dermal endothelial cells.

P-Selectin expressed on endothelial cells contributes to acute and chronic inflammation by promoting leukocyte tethering/rolling. Despite increasing evidence of P-selectin expression on human umbilical vein endothelial cells in vitro, the regulatory mechanisms of P-selectin expression on dermal endothelial cells in skin diseases are not fully understood. Here, we demonstrate increased expression of P-selectin in dermal vessels of regional skin in urticaria and atopic dermatitis. The present in vitro analyses with human dermal microvascular endothelial cells (HDMECs) revealed that histamine rapidly induced P-selectin expression. Interleukin (IL)-4 and IL-13 induced prolonged expression of surface P-selectin by HDMECs. A combination of tumor necrosis factor-alpha and IL-4 inhibited P-selectin expression. Pretreatment of HDMECs with tumor necrosis factor-alpha followed by incubation with IL-4 markedly increased P-selectin expression. Notably, incubation with substance P alone induced prolonged P-selectin expression. Activation of STAT6 appears to be a key factor in P-selectin expression induced by substance P and IL-4 because treatment with STAT6 decoy oligodeoxynucleotides significantly inhibited P-selectin expression. The present results indicate that novel, complex mechanisms are involved in endothelial P-selectin expression in the skin. STAT6 in dermal endothelial cells appears to be a potent target for controlling cellular infiltrate in allergic and/or neuroinflammatory skin diseases.

Base Sequence↗
PubMed2005

Genomic alterations in primary cutaneous melanomas detected by metaphase comparative genomic hybridization with laser capture or manual microdissection: 6p gains may predict poor outcome.

To clarify the correlation of genomic alterations with clinical and histological features, we performed metaphase comparative genomic hybridization analysis on 20 primary cutaneous melanomas, which were obtained by laser capture or manual microdissection, and 16 melanoma cell lines. There were no differences in the average number of aberrations between acral melanomas (AM) and non-AM, although gains of 5q and 11q13 were more frequent (P=0.05) and 10q loss was less frequent (P=0.01) in AM than in non-AM. Although tumor thickness is considered a measurable estimate of clinical expression, there were no differences in the average number of aberrations among 4 groups, classified by thickness of the tumor. While the majority of aberrations were equally distributed among the 4 groups, 6p gains were found only in the thickest tumors. Patients with 6p or 1q gains had a lower overall survival rate than those without them (P=0.0002 or P=0.013). While gains of 1q, 2q, 3p, 3q, 7q, 20p, and 20q were more frequent in the cell lines than in the primary tumors (P<0.01), losses of 6q, 9p, 10p, and 10q were equally found in both cell lines and primary tumors. The present study showed that chromosomal aberrations had already occurred in the thinner tumors, and that 6p and 1q gains may be a prognostic factor.

Adult↗
PubMed2005

Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells.

The recruitment of basophils into the sites of allergic inflammation is often observed. However, no definitive evidence has been provided that basophils are crucially involved in the pathogenesis of chronic allergic disorders. Here, we show that basophils are responsible for the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. A single subcutaneous injection of multivalent antigens elicited not only immediate- and late-phase ear swelling but also delayed-onset ear swelling with massive eosinophil infiltration in mice sensitized with antigen-specific IgE. Mast cells were essential for the immediate- and late-phase ear swelling but dispensable for the delayed one. T cells were also dispensable for the latter. Transfer of FcRI-expressing basophils into FcRI-deficient mice restored the development of the delayed-onset allergic inflammation. These findings indicate a novel mechanism of development of chronic allergic inflammation that is induced by basophils through the interaction of antigen, IgE, and FcRI.

Animals↗
PubMed2005

Synthesis of {alpha}(1,3) fucosyltransferases IV- and VII-dependent eosinophil selectin ligand and recruitment to the skin.

Selectins mediate the initial adhesion of leukocytes to endothelial cells in many contexts of inflammation-dependent leukocyte recruitment. The glycans that contribute to P- and E-selectin counterreceptor activity arise through glycosylation reactions in which the terminal steps are catalyzed by alpha(1,3) fucosyltransferases (FTs). We examined how selectin ligand activities are controlled in eosinophils by characterizing FT expression profiles and regulatory mechanisms in eosinophils isolated from human blood. We found that FT-IV and FT-VII mRNAs were up-regulated by transforming growth factor-beta1, but the FT-IV transcript consistently predominated in eosinophils. To further define the physiological role of FT-IV and FT-VII in expression of eosinophil selectin ligand, we characterized models of dermal eosinophilia in FT-IV- and/or FT-VII-deficient mice in vivo. FT-IV deficiency yielded a significant decrease in eosinophil recruitment to the skin. Likewise, deficiency of FT-VII also yielded a decrease in eosinophil recruitment. Eosinophil recruitment that remained in the absence of FT-VII was further inhibited by blocking P- or E-selectin and was essentially absent in mice deficient in both enzymes. These observations indicate that FT-IV and FT-VII are both important contributors to selectin-dependent eosinophil recruitment to the skin and may represent therapeutic targets for treating diseases in which eosinophil recruitment contributes to pathophysiology.

Animals↗
PubMed2005

Infectious urticaria with purpura: a mild subtype of urticarial vasculitis?

Urticaria is characterized by transient wheals. We report here five cases with long-lasting urticarial lesions persisting for more than 24 hours. Each lesion left purpura after fading. There was no systemic involvement. C-reactive protein and serum levels of complement were elevated or normal. Histologically, marked infiltration by eosinophils and neutrophils with karyorrhexis in the perivascular and intercollagenous spaces was observed, but there was no evidence of vasculitis (venulitis). Skin symptoms were resistant to systemic corticosteroids. In contrast, treatment of underlying bacterial infections resulted in marked improvement of skin lesions. E-selectin, VCAM-1 and ICAM-1 were expressed on endothelial cells. Marked deposition of C3a, C5a, neutrophil elastase and major basic protein in the dermis was observed. These urticarial lesions provoked by bacterial infections seem to lie on the continuum between urticaria and urticarial vasculitis.

Adult↗
PubMed2005

Clinical analysis of 21 patients with psoriasis arthropathy.

Psoriasis arthropathy (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis with psoriasis. In this study, clinical, laboratory and radiographic signs of 21 patients (12 males and 9 females), mean age of 42.2 years old, with PsA were assessed. The clinical forms defined by Moll and Wright revealed that oligoarticular pattern was most commonly observed in ten patients (47.6%), followed by polyarticular (5 patients), distal (3 patients), spondyloarthropathy (2 patients), and mutilans (1 patient). Positive rheumatoid factor was detected in three patients and antinuclear antibodies in eight patients, suggesting the involvement of immunological disregulation in this disorder. Twelve patients were onychopathic, of whom 11 showed distal interphalangeal (DIP) joint arthritis. Based on radiologic observation, spur formation of the calcaneus (1 patient) and destructive changes of the articulatio coxa (1 patient) were seen, in addition to the findings such as joint space narrowing, erosive changes, resorptive changes and 'pencil-in-cup' appearances. Non-steroidal anti-inflammatory drugs (NSAIDs) were used in all cases for the control of joint pain, solely or in combination with immunomodulatory drugs such as bucillamine, sulfasalazine, methotrexate, cyclosporin, etretinate, and mizoribine. However, some of those drugs were often ineffective for the joint pain, while effective for cutaneous psoriasis. Immunohistological studies of the biopsied synovial tissues from two patients showed increased expressions of CD45RO and HLA-DR, suggesting that the vast majority of inflammatory cells are mature and activated T-cells. Parallel immunostaining using the involved psoriatic skin from one of the patients also showed enhanced expression of CD45RO, but less expression of HLA-DR as compared with its expression in the synovium. On the other hand, cutaneous leukocyte antigen (CLA) was abundantly detected in the inflammatory cells in the lesional skin, although less expressed in the synovium. These results are consistent with earlier observations suggesting a different subpopulation of inflammatory cells in the skin than the joint.

Adult↗
PubMed2005

Psoriasis arthropathy and HLA-B51: report of 5 cases.

Psoriasis arthropathy (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis with psoriasis. Although the precise mechanisms of PsA still remain obscure, several genetic and environmental factors have been suggested to play important roles. HLA-B51 has been strongly associated with Behçet's disease; however, its association with PsA has not been documented. We describe herein five Japanese patients (4 males and 1 female) with PsA and positive for HLA-B51. The clinical forms defined by Moll and Wright revealed that the polyarticular pattern was noted in two cases, and oligoarticular, distal, and spondyloarthropathy patterns were noted in one case each. Positive rheumatoid factor was detected in one patient, and antinuclear antibody in two patients. The other HLA subclasses were A2 and A31 in 3 cases, respectively. HLA-B51 was detected in 5 out of 17 patients with PsA examined in our department; in contrast, HLA-B51 was not detected in 17 patients with psoriasis vulgaris. Our observations suggest that HLA-B51 may play a role in the pathogenesis of PsA in the Japanese population.

Adult↗
PubMed2005

Multiple cutaneous fibrous histiocytomas in association with systemic lupus erythematosus.

Cutaneous fibrous histiocytomas are usually regarded as superficial lesions and commonly known as dermatofibromas; however, unusual cases histologically showing fibrohistiocytic proliferation extending into the deeper dermis or subcutaneous tissues are occasionally experienced. Some authors propose this type as benign fibrous histiocytoma of the skin, distinct from dermatofibroma. We describe herein a case of systemic lupus erythematosus (SLE) who developed multiple nodules on the face, trunk and extremities. The nodule on the forehead did not present a typical clinical appearance of dermatofibroma, and histopathological examination showed fibrohistiocytic proliferation with a storiform pattern extending into the deep dermis and subcutaneous tissues. By contrast, histology of the nodule on the abdomen showed fibrohistiocytic proliferation confined to the dermis and compatible with dermatofibroma. Although multiple dermatofibromas are occasionally seen in patients with SLE, benign fibrous histiocytoma of the skin showing deeper invasion than dermatofibroma is rarely associated with SLE.

Adult↗