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Biomedical subjects

Ryuhei Okuyama

Publications and source records attributed to Ryuhei Okuyama.

At least 19 recordsLinked to original sources
PubMed2006

Epidermal-type fatty acid binding protein as a negative regulator of IL-12 production in dendritic cells.

Fatty acids and their metabolites have recently been shown to modulate various functions of dendritic cells (DCs) including their differentiation and cytokine production, although the mechanisms underlying their cellular functions are not fully understood. In view of our previous finding that epidermal-type fatty acid binding protein (E-FABP) was exclusively expressed in splenic DCs among FABP family, we examined the phenotype of E-FABP-null mutant mice in order to elucidate the functional significance of E-FABP expression in DCs. Although E-FABP-null mutant mice showed no apparent abnormalities in the population density and subset distribution of DCs as well as the microscopic morphology in the spleen, DCs isolated from E-FABP-null spleen showed enhanced production of IL-12p70, a key cytokine for innate immune responses, in response to appropriate stimuli as compared with wild-type. In real-time PCR, the expression level of IL-12p35 mRNA after LPS stimuli was much higher in mutant DCs when compared with wild-type, while no apparent change of IL-12p40 mRNA level was detected. Phosphorylated forms of p38 mitogen-activated protein kinase (p38MAPK) and IkappaB-alpha, molecules critical for IL-12 production, were detected at higher levels in E-FABP-null-mutant DCs after LPS stimuli when compared with wild-type counterparts. Collectively, it is suggested that E-FABP may be a novel negative regulator of IL-12 production in DCs, and this regulation may be exerted via its involvement in the p38MAPK-mediated transcription of IL-12p35.

Animals↗
PubMed2006

Decreased keratinocyte motility in skin wound on mice lacking the epidermal fatty acid binding protein gene.

Fatty acids are shown to be important in various skin functions. Fatty acid binding protein (FABP) is postulated to serve as a lipid shuttle, solubilizing hydrophobic fatty acids and delivering them to the appropriate metabolic system. Among the FABP family proteins, epidermal-type FABP (E-FABP) is solely expressed in keratinocyte but its specific role in skin is not yet fully established. We found an elevated expression of E-FABP in regenerative keratinocytes of healing wounds. However, E-FABP null mice showed no marked differences compared to wild type mice in the process of wound closure, in vivo. On the other hand, in keratinocyte culture, E-FABP gene disruption decreased the cell motility, but did not affect the cell proliferation. E-FABP deletion may be compensated for in vivo by the microenvironment comprised of various cells such as fibroblasts and endothelial cells around the wound. Our analyses suggest that the E-FABP elevation may be necessary for the activation of cell motility within regenerative epidermis during wound healing.

Animals↗
PubMed2006

The accelerating effect of histamine on the cutaneous wound-healing process through the action of basic fibroblast growth factor.

This study revealed that the absence of histamine in histidine decarboxylase gene-knockout (HDC(-/-)) mice resulted in delayed cutaneous wound healing and that exogenously administered histamine compensated this process. With the overproduction of histamine in HDC gene-transgenic mice, the healing was accelerated compared to the HDC(+/+) mice. These results indicate that histamine positively accelerated the cutaneous wound healing. Macrophage recruitment and angiogenesis at the wound edge were specifically impaired in HDC(-/-) mice, and histamine-treated wounds in HDC(-/-) mice demonstrated increased macrophage recruitment and angiogenesis. The amount of basic fibroblast growth factor (bFGF) in protein level at the wound edge was higher in HDC(+/+) mice, especially on the 3rd and 5th day of wound healing compared to those in HDC(-/-) mice. Topically administered SU5402, a specific antagonist to fibroblast growth factor receptor-1 tyrosine kinase, to the wound surface suppressed the wound healing in HDC(+/+) mice but not in HDC(-/-) mice. Moreover, SU5402 reduced macrophage recruitment and angiogenesis in HDC(+/+) mice. From these observations, it was concluded that the accelerated wound-healing activity of histamine was mediated by the activity of bFGF, which leads to angiogenesis, and macrophage recruitment in the wound-healing process.

Angiogenesis Inhibitors↗
PubMed2006

Generalized mucinosis in a patient with erythroderma.

We describe an 81-year-old Japanese patient with erythroderma overlapping with widespread and symmetrical deposits of mucin in the upper dermis. Clinically, the mucinous lesions on the nape and upper trunk were localized papular mucinosis. Histologically, there was a perivascular infiltrate of lymphohistiocytic cells mingled with plasma cells in the upper dermis but no sclerosis. Immunohistochemical staining revealed that more than 90% of these infiltrating plasma cells produced immunoglobulin lambda-chain. Both the erythroderma and generalized mucinosis responded to topical steroid and PUVA therapy. To the best of our knowledge, this is the first case of erythroderma accompanied by generalized mucinosis.

Administration, Cutaneous↗
PubMed2006

Cytomegalovirus infection complicating immunosuppressive therapy for dermatomyositis.

The occurrence of opportunistic infections is not rare during the treatment of connective tissue diseases, including dermatomyositis because of the patient's immunosuppression. We describe here cytomegalovirus (CMV) infection that affected two of our patients with dermatomyositis. CMV infection has not been considered to be a frequent event in dermatomyositis, and its significance for disease progression has not been sufficiently recognized. Our case reports demonstrate the importance of close monitoring of such patients and prompt initiation of appropriate therapy to manage a suspected CMV infection.

Aged↗
PubMed2005

Development of a novel Ag-specific immunotherapy using CpG oligodeoxynucleotides in a new, unique mouse cutaneous eosinophilic inflammation model.

The number of patients with severe atopic dermatitis (AD) has been on the rise recently. We are therefore urgently in need of a treatment that can suppress Th2 cell-mediated responses in an Ag-specific fashion. Oligodeoxynucleotides (ODN)containing CpG motifs (CpG ODN) have been highlighted as immunomodulators that reduce Th2-mediated responses. To determine the effect of CpG ODN on Th2-mediated skin inflammation, we first developed a reproducible murine model of protein Ag-induced eosinophilic inflammation that is accompanied by epidermal acanthosis and increased serum IgE levels as seen in AD. In this model we found that treatment with CpG ODN during epicutaneous sensitization in previously i.p.-primed mice prevented the development of Th2-mediated responses. Furthermore, to evaluate the therapeutic effect of CpG ODN on established eosinophilic inflammation, mice were treated with a course of the immunotherapy at a skin site remote from the area of Ag application prior to the second 1-wk epicutaneous exposure to Ag. Therapeutic treatment with CpG ODN plus Ag, but not that with CpG ODN alone, could reverse the established eosinophilic inflammation. The presented results provide strong evidence for the feasibility of a novel Ag-specific immunomodulator to treat cutaneous eosinophilic inflammation such as that characteristically found in patients with severe AD.

Animals↗
PubMed2005

Myxofibrosarcoma (myxoid malignant fibrous histiocytoma) showing cutaneous presentation: report of two cases.

Myxofibrosarcoma or myxoid malignant fibrous histiocytoma is one of the most common fibroblastic sarcomas in older patients. It is characterized by a tendency for predominantly subcutaneous, multinodular, diffusely infiltrative growth, which may extend to the overlying dermis and present as a cutaneous lesion. Histologically, it comprises a spectrum ranging from hypocellular low-grade myxoid to high-grade pleomorphic sarcoma. Because the dermal presentation usually appears relatively banal, accurate diagnosis is sometimes challenging. In this report, we present two cases of myxofibrosarcoma with dermal involvement.

Aged↗
PubMed2004

High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism.

Embryonic cells are expected to possess high growth/differentiation potential, required for organ morphogenesis and expansion during development. However, little is known about the intrinsic properties of embryonic epithelial cells due to difficulties in their isolation and cultivation. We report here that pure keratinocyte populations from E15.5 mouse embryos commit irreversibly to differentiation much earlier than newborn cells. Notch signaling, which promotes keratinocyte differentiation, is upregulated in embryonic keratinocyte and epidermis, and elevated caspase 3 expression, which we identify as a transcriptional Notch1 target, accounts in part for the high commitment of embryonic keratinocytes to terminal differentiation. In vivo, lack of caspase 3 results in increased proliferation and decreased differentiation of interfollicular embryonic keratinocytes, together with decreased activation of PKC-delta, a caspase 3 substrate which functions as a positive regulator of keratinocyte differentiation. Thus, a Notch1-caspase 3 regulatory mechanism underlies the intrinsically high commitment of embryonic keratinocytes to terminal differentiation.

Animals↗
PubMed2004

Peritumoral CpG oligodeoxynucleotide treatment inhibits tumor growth and metastasis of B16F10 melanoma cells.

Although melanoma mostly affects the skin, it is notorious for its propensity to easily develop metastasis. Metastatic melanoma is highly resistant to a variety of therapies. We examined the anti-metastatic potential of peritumoral monotherapy against murine cutaneous B16F10 melanoma with synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs. We demonstrated that repeated peritumoral injections of CpG ODN significantly reduced skin tumor size. Peritumoral CpG ODN-treatment of skin tumors prevented the development of pulmonary B16F10 colonies. Adoptive transfer of splenocytes obtained from CpG ODN-treated mice markedly reduced the number of previously established pulmonary colonies in recipient naïve mice. T-lymphocyte depletion studies indicated that the anti-metastatic effect was dependent on both CD4+ and CD8+ T cells. These results suggest that CpG ODN are promising as a preventive and therapeutic anti-metastatic measure against melanoma.

Adoptive Transfer↗
PubMed2004

A dynamic model of keratinocyte stem cell renewal and differentiation: role of the p21WAF1/Cip1 and Notch1 signaling pathways.

We present here a dynamic model of functional equilibrium between keratinocyte stem cells, transit amplifying populations and cells that are reversibly versus irreversibly committed to differentiation. According to this model, the size of keratinocyte stem cell populations can be controlled at multiple levels, including relative late steps in the sequence of events leading to terminal differentiation and by the influences of a heterogeneous extra-cellular environment. We discuss how work in our laboratory, on the interconnection between the cyclin/CDK inhibitor p21WAF1/Cip1 and the Notch1 signaling pathways, provides strong support to this dynamic model of stem cell versus committed and/or differentiated keratinocyte populations.

Animals↗