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Biomedical subjects

Kunihiko Tamaki

Publications and source records attributed to Kunihiko Tamaki.

At least 19 recordsLinked to original sources
PubMed2007

Treatment of 153 Japanese patients with Q-switched alexandrite laser.

We have recently used Q-switched alexandrite laser for the treatment of various kinds of pigmented skin lesions. We retrospectively compared therapeutic outcomes of 153 Japanese patients who consulted our department. This approach was not very efficient for nevus spilus/café-au-lait spots, which seemed laser-resistant, especially when the pigmentation had appeared after 1 year of age, was treated after 5 years of age, was located on the face, was oval with a smooth border, and the patient was male. This approach was equally effective for senile lentigo, nevus of Ota, and Mongolian spots, but less effective for acquired bilateral nevus of Ota-like macules. Some patients with sacral Mongolian spots or those with light-colored, senile lentigo developed severe post-inflammatory hyperpigmentation after treatment. As a whole, good therapeutic outcome was achieved after multiple treatment sessions. However, the use of other lasers or other treatment modalities should be considered to treat nevus spilus/café-au-lait spots.

Beryllium↗
PubMed2007

Serum anti-Fcgamma receptor autoantibodies in patients with alopecia areata.

Although anti-Fcgamma receptor antibodies (Abs) are detected in various autoimmune diseases, there have been no studies about the anti-Fcgamma receptor Abs in alopecia areata (AA). To detect the anti-Fcgamma receptor Abs in patients with AA and their clinical correlations, Serum samples from 72 patients with AA and 23 normal controls were examined by enzyme-linked immunosorbent assay assessing anti-Fcgamma receptor Ab levels. Anti-Fcgamma receptor I Abs were significantly frequently detected in patients with AA compared with normal controls. Furthermore, the detection of anti-Fcgamma receptor I Abs significantly inversely correlated with the disease duration. These results suggest that anti-Fcgamma receptor I Ab and Fcgamma receptor I play an important role in the regulation of AA, are useful for a marker of the disease prognosis and are worth intense research for the reasonable and specific therapy of AA.

Adolescent↗
PubMed2006

Isolation of murine hair-inducing cells using the cell surface marker prominin-1/CD133.

Hair is a mini-organ in which dermal papilla (DP) cells play important roles in hair follicle morphogenesis and formation via interactions with epithelial cells. DP cells have previously been difficult to analyze because of the lack of a specific surface marker. We have demonstrated that prominin-1/CD133 (CD133) is a useful marker for murine DP cells. DP cells express CD133 during the early anagen stage (active growth phase) not only during hair morphogenesis, but also during the growth phase of hairs after birth. Gene expression and flow cytometric analysis revealed that CD133-positive (+) cells in the skin possess the characteristics of DP cells. The CD133(+) cells isolated from embryonic or adult skin-induced new hair follicles in vivo when they were transplanted into nude mice mixed with embryonic epithelial cells, but CD133-negative (-) cells could not. We propose that the CD133 is a novel surface marker useful for collecting DP cells in the anagen stage and for analyzing the function of DP.

AC133 Antigen↗
PubMed2006

Clinical features of scleroderma patients with contracture of phalanges.

Contracture of phalanges (CP) is a frequent complication of patients with systemic sclerosis (SSc). The objective of this study was to examine the prevalance of CP in patients with SSc and investigate the clinical and laboratory features of SSc patients with CP. Three hundred and fifty patients with SSc were examined. CP was found in 164 of the 350 patients (47%) with SSc. The prevalence of oesophageal involvement, pulmonary fibrosis or heart involvement was significantly greater in the patients with CP than that in those without CP. Our study suggested that the presence of CP may be a marker of oesophageal involvement, pulmonary fibrosis and heart involvement.

Adult↗
PubMed2006

Anti-p53 antibodies in patients with dermatomyositis/polymyositis.

Dermatomyositis/polymyositis (DM/PM), which is often accompanied by various immunological abnormalities, was reported to be associated with an increased incidence of malignancies. In this study, we analyzed serum levels of anti-p53 antibody (anti-p53 Ab) in DM/PM patients and in normal controls. Serum levels of anti-p53 Abs were significantly higher in DM/PM patients than those in healthy controls. However, there was no significant difference between serum levels in patients with malignancies and those in patients without malignancies. Anti-p53 Abs were positive in 13% (4 out of 31) of the DM/PM patients. Of these four patients, only one had an internal malignancy. Immunoglobulin G levels were significantly higher in patients positive for anti-p53 Ab than those who were not. These results seemed to suggest that the presence of anti-p53 Abs in DM/PM patients is due to immunological abnormalities in this disease.

Adult↗
PubMed2006

Epidermal growth factor up-regulates transforming growth factor-beta receptor type II in human dermal fibroblasts via p38 mitogen-activated protein kinase pathway.

TGF-beta receptors (TbetaRs) are serine/threonine kinase receptors that bind to TGF-beta and propagate intracellular signaling through Smad proteins. TbetaRs are repressed in some human cancers and expressed at high levels in several fibrotic diseases. We demonstrated that epidermal growth factor (EGF) up-regulates type II TGF-beta receptor (TbetaRII) expression in human dermal fibroblasts. EGF-mediated induction of TbetaRII expression was inhibited by the treatment of fibroblasts with a specific p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, whereas MEK inhibitor PD98059 did not block the up-regulation of TbetaRII by EGF. EGF induced the TbetaRII promoter activity, and this induction was significantly blocked by SB203580, but not by PD98059. The overexpression of the dominant negative form of p38alpha or p38beta significantly reduced the induction of TbetaRII promoter activity by EGF. These results indicate that the EGF-mediated induction of TbetaRII expression involves the p38 MAPK signaling pathway. The EGF-mediated induction of TbetaRII expression may participate in a synergistic interplay between EGF and TGF-beta signaling pathway.

Cells, Cultured↗
PubMed2006

Macrophage-derived chemokine (MDC)/CCL22 produced by monocyte derived dendritic cells reflects the disease activity in patients with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a recurrent inflammatory skin disease characterized by high serum levels of IgE and Th2-type cytokines such as IL-4, IL-5 or IL-13. Chemokines attract leukocytes in inflamed tissues. We have previously found that thymus and activation regulated chemokine (TARC)/CCL17 and macrophage-derived chemokine (MDC)/CCL22 are highly secreted in the plasma levels of AD patients. Dendritic cells (DCs) are antigen-presenting cells that are divided into two subgroups including monocyte derived DCs (MoDCs) and plasmacytoid DCs (pDCs). OBJECTIVES: The aim of the study was to elucidate CCL17 and CCL22 production by MoDCs in AD patients, psoriasis vulgaris (PsV) patients and healthy controls (HC). METHODS: MoDCs were obtained from AD patients, PsV patients or HC and were cultured. In addition, the chemokine levels were measured in the supernatants. RESULTS: We found that the CCL22 levels produced by MoDCs in AD patients to be significantly higher than those of PsV patients and HC. There was a significant correlation between the CCL22 levels produced by MoDCs and the SCORAD index. No significant difference in the CCL17 levels produced by MoDCs was detected among AD patients, PsV patients or HC. Immunosuppressive drugs such as dexamethasone (Dex), tacrolimus and cyclosporine (Cys) inhibited the CCL22 production by MoDCs in the AD patients. CONCLUSION: These data suggest that the CCL22 level produced by MoDCs thus reflects the disease activity of AD and it may also play an important role regarding the production of CCL22 in the pathogenesis of AD.

Adolescent↗
PubMed2006

Role of Langerhans cells in cutaneous protective immunity: is the reappraisal necessary?

Langerhans cells (LC) are constantly exposed to external antigens and pathogens, and they are the cutaneous counterpart of dendritic cells (DC). DC not only act as professional antigen presenting cells to induce antigen-specific T cells for adaptive immune responses, but they also initiate a cascade of innate immune responses by sensing these danger signals. However, recent studies challenge the classical paradigm to position LC in the center of cutaneous immunity. Although LC express toll-like receptors (TLRs) that recognize bacterial and viral products, exposure to pathogen-associated TLR ligands triggers neither sufficient LC maturation nor good production of cytokines and chemokines. LC also lack the ability to produce IFN-gamma by any stimuli, and together with the characteristics of LC that are prone to produce Th2-type chemokines and to produce much less IL-12 in the presence of keratinocyte-derived GM-CSF, LC primarily may not have the character to induce Th1- and Tc1-type immune responses necessary for protective cellular immunity. Moreover, LC maturation is inhibited, rather than enhanced, by type I IFNs that are abundantly produced in viral infections in the skin microenvironment. Finally, recent data suggest that LC may not directly present viral antigens to T cells for their activation in mouse models of cutaneous viral infection. The alternative player in protective immune responses may be surrounding keratinocytes, which may modulate LC functions indirectly. Dermal DC may also participate in this scheme. Further studies are required to clarify the role of LC in their interplay with keratinocytes and other DC subsets, and to draw the entire picture of the cutaneous immune system against pathogens.

Animals↗
PubMed2006

Thymus and activation regulated chemokine (TARC)/CCL17 and skin diseases.

Thymus and activation-regulated chemokine (TARC)/CCL17 is constitutively expressed in the thymus and is produced by dendritic cells (DC), endothelial cells, keratinocytes (KC) and fibroblasts. TARC is designated a Th2 type chemokine since it binds to CCR4. We review the pathogenic role of TARC in skin diseases such as atopic dermatitis (AD), bullous pemphigoid (BP) and mycosis fungoides (MF) focusing on epidermal KC and Langerhans cells (LC), which are epidermal DC. We have determined that serum TARC levels sharply reflect the disease activity of AD, which is thought to be a Th2-dominant inflammatory skin disease especially in the acute phase. Serum TARC levels are also related to the disease activity of BP, which is a blistering autoimmune skin disease, and MF, which is a cutaneous T-cell lymphoma, but very high serum TARC levels are only seen in a limited number of various other skin diseases. TARC may be a useful laboratory marker for the diagnosis of AD, especially cases which are moderate to severe, and for the evaluation of disease activity of AD. IL-4 and TGF-beta1 downregulate TNF-alpha and IFN-gamma induced TARC production in the human KC cell line, HaCaT cells, while IL-4 upregulates, and IFN-gamma downregulates TARC production by mouse LC. Because TARC and its receptor CCR4 are believed to play important roles in the pathogenesis of AD, BP and MF, TARC and CCR4 may be possible future targets for therapy of these diseases.

Chemokine CCL17↗
PubMed2006

The repeat domain of the melanosomal matrix protein PMEL17/GP100 is required for the formation of organellar fibers.

Over 125 pigmentation-related genes have been identified to date. Of those, PMEL17/GP100 has been widely studied as a melanoma-specific antigen as well as a protein required for the formation of fibrils in melanosomes. PMEL17 is synthesized, glycosylated, processed, and delivered to melanosomes, allowing them to mature from amorphous round vesicles to elongated fibrillar structures. In contrast to other melanosomal proteins such as TYR and TYRP1, the processing and sorting of PMEL17 is highly complex. Monoclonal antibody HMB45 is commonly used for melanoma detection, but has the added advantage that it specifically reacts with sialylated PMEL17 in the fibrillar matrix in melanosomes. In this study, we generated mutant forms of PMEL17 to clarify the subdomain of PMEL17 required for formation of the fibrillar matrix, a process critical to pigmentation. The internal proline/serine/threonine-rich repeat domain (called the RPT domain) of PMEL17 undergoes variable proteolytic cleavage. Deletion of the RPT domain abolished its recognition by HMB45 and its capacity to form fibrils. Truncation of the C-terminal domain did not significantly affect the processing or trafficking of PMEL17, but, in contrast, deletion of the N-terminal domain abrogated both. We conclude that the RPT domain is essential for its function in generating the fibrillar matrix of melanosomes and that the luminal domain is necessary for its correct processing and trafficking to those organelles.

Amino Acid Sequence↗
PubMed2006

Involvement of alphavbeta5 integrin in the establishment of autocrine TGF-beta signaling in dermal fibroblasts derived from localized scleroderma.

Localized scleroderma (LSc) is a connective tissue disorder limited to skin and subcutaneous tissue, which may share pathogenic processes with systemic sclerosis (SSc). We previously demonstrated that upregulated expression of integrin alphavbeta5 might contribute to autocrine TGF-beta signaling in SSc fibroblasts. Based on these data, we presently focused on alphavbeta5 and assessed its involvement in pathogenesis of LSc. We initially demonstrated that LSc fibroblasts might be activated by the stimulation of autocrine TGF-beta. Consistent with SSc fibroblasts, expression levels of alphavbeta5 were elevated in LSc fibroblasts in vitro and in vivo. Anti-alphavbeta5 antibody partially reversed expression levels of type I procollagen and MMP-1 and constitutive DNA-Smad3 binding in LSc fibroblasts. In LSc fibroblasts pretreated with antisense TGF-beta1, exogenous latent TGF-beta1 stimulation increased expression of type I procollagen in an alphavbeta5-dependent manner. The luciferase activities of TMLC cells, Mv1Lu cells stably expressing a portion of the plasminogen activator inhibitor 1 promoter, co-cultured with LSc fibroblasts were significantly elevated compared with those co-cultured with normal fibroblasts and were significantly reduced in the presence of anti-alphavbeta5 antibody. Anti-alphavbeta5 antibody reversed the myofibroblastic features of LSc fibroblasts. These results indicate that upregulated expression of alphavbeta5 contributes to autocrine TGF-beta signaling in LSc fibroblasts.

Antibodies↗
PubMed2006

Potential regulatory elements of the constitutive up-regulated alpha2(I) collagen gene in scleroderma dermal fibroblasts.

The promoter activity of the full-length alpha2(I) collagen gene is higher in scleroderma fibroblasts, when compared to normal fibroblasts. In this study, to investigate the molecular mechanisms up-regulating the expression of the alpha2(I) collagen gene in scleroderma dermal fibroblasts more clearly, we compared promoter activities of serial 5'-deletion mutants and the substitution mutants of the alpha2(I) collagen promoter constructs between normal and scleroderma fibroblasts. The transient transfection assays using a series of 5'-deletions of the promoter revealed that the up-regulated fold-increase in scleroderma fibroblasts relative to that in normal fibroblasts was significantly decreased by the removal of bp -353 to -264 fragment or bp -264 to -186 fragment. The substitution mutations introduced into binding sites of Sp1 (bp -303 and -271), Ets1 (bp -285 and -282), as well as Smad (bp -263 and -258) also abrogated the fold-increase in promoter activity in scleroderma fibroblasts synergistically. A DNA affinity precipitation assay showed that the binding activity of Ets1 as well as Smad3 to their binding sites was increased in scleroderma fibroblasts compared with normal cells. Taken together, our promoter analysis emphasized that Ets1 form a transcriptionally active complex with Smad and Sp1 by autocrine transforming growth factor (TGF)-beta signaling, leading to the intrinsic up-regulation of alpha2(I) collagen promoter activity in scleroderma fibroblasts. The blockade of autocrine TGF-beta signaling is thought to be one of the most reliable approaches in the treatment of scleroderma, and further study targeting Ets1, Smad or Sp1 may contribute to this blockade.

Collagen↗
PubMed2006

Epidermal growth factor affects the synthesis and degradation of type I collagen in cultured human dermal fibroblasts.

EGF and type I collagen are known to play important roles in wound healing. In the present study, we demonstrated that EGF down-regulates the expression of type I procollagen protein as well as alpha2(I) collagen mRNA in cultured human dermal fibroblasts. EGF induced the degradation of type I procollagen protein in conditioned medium through the up-regulation of MMP-1 expression. EGF down-regulated alpha2(I) mRNA expression partially at the post-transcriptional level by reducing the mRNA stability. In contrast, EGF up-regulated MMP-1 mRNA expression mostly at the transcriptional level, in that it had a stimulatory effect on MMP-1 promoter activity, but no effect on MMP-1 mRNA stability. The MEK/ERK signaling pathway was shown to be involved in EGF-mediated type I collagen and MMP-1 expression.

Collagen Type I↗
PubMed2006

B cell antigen receptor and CD40 differentially regulate CD22 tyrosine phosphorylation.

Cell surface molecules on lymphocytes positively or negatively modulate the Ag receptor signaling, and thus regulate the fate of the cell. CD22 is a B cell-specific cell surface protein that contains multiple ITIMs in the cytoplasmic tail, and critically regulates B cell activation and survival. CD22 regulation on B cell signaling is complex because CD22 can have both positive and negative roles in various contexts. We generated phosphospecific polyclonal Abs reacting four major CD22 tyrosine motifs (Y762, Y807, Y822, and Y842) and analyzed the pattern and intensity of phosphorylation of these tyrosine residues. The tyrosine motifs, Y762, Y822, and Y842, are considered as ITIM, whereas the other, Y807, is suggested to be important for Grb2 recruitment. Approximately 10% of the four tyrosine residues were constitutively phosphorylated. Upon anti-IgM ligation, CD22 Y762 underwent most rapid phosphorylation, whereas all four tyrosine residues were eventually phosphorylated equally at approximately 35% of all CD22 molecules in the cell. By contrast, anti-CD40 stimulation specifically up-regulated anti-IgM-induced phosphorylation of tyrosines within two ITIM motifs, Y762 and Y842, which was consistent with in vivo finding of the negative role of CD22 in CD40 signaling. Thus, CD22 phosphorylation is not only quantitatively but also qualitatively regulated by different stimulations, which may determine the outcome of B cell signaling.

Amino Acid Sequence↗
PubMed2006

Rheumatoid factor isotypes in mixed connective tissue disease.

Mixed connective tissue disease (MCTD) is a connective tissue disorder that is often accompanied by various immunological abnormalities. In this study, we analyzed serum levels of rheumatoid factor (RF) isotypes in patients with MCTD and in normal controls to determine if any of these isotypes reflects the severity of the disease. IgM-RF, IgG-RF, and IgA-RF were positive in 48, 38, and 33% of the patients, respectively. The frequency of positive anti-SS-A antibody and decrease in white blood cell counts were significantly greater in patients with elevated IgA-RF levels than that in those with normal levels. These results suggest that the presence of RF isotypes can be regarded as one of the various immunological abnormalities of MCTD.

Adult↗
PubMed2006

CCL17 transgenic mice show an enhanced Th2-type response to both allergic and non-allergic stimuli.

CC chemokine ligand (CCL)17 is implicated in the pathogenesis of atopic dermatitis (AD). To study the effect of CCL17 produced by keratinocytes (KC) during inflammation, we created transgenic (Tg) mice in which CCL17 is overexpressed in KC. Th2-type contact hypersensitivity (CHS) was enhanced and Th1-type CHS was suppressed in these mice. Increased numbers of CC chemokine receptor (CCR)4(+) cells and mast cells infiltrated in Tg mice. Levels of IL-4 mRNA were higher and those of IFN-gamma mRNA were lower in both acute and chronic CHS. Higher levels of serum IgE were observed after CHS. Numbers of CCR4(+) cells among PBMC were increased in Tg mice challenged acutely on the trunk. Chronic irritation with croton oil induced dermatitis and an elevation of serum IgE levels. Tg mice showed enhanced ear swelling after tape stripping. CCL17 was thought to modify the inflammation caused by sensitizing reagents as well as irritant reagents by attracting CCR4(+) cells into the lesional skin and creating a Th2-dominant condition. AD-like conditions such as increased number of mast cells and elevated levels of serum IgE were observed. Thus, CCL17 may participate in the pathogenesis of skin diseases such as AD by regulating both allergic and irritant inflammation.

Acute Disease↗
PubMed2006

Platelet derived growth factor induced tenascin-C transcription is phosphoinositide 3-kinase/Akt-dependent and mediated by Ets family transcription factors.

Previous studies have identified several cytokines as inducers of tenascin-C (TN-C) expression in various tissue culture systems. However, the signaling pathways of the regulation of TN-C expression are almost unknown. In this study, we clarified the molecular mechanism(s) underlying the regulation of the TN-C gene by platelet derived growth factor (PDGF) in cultured human dermal fibroblasts. PDGF induced the expression of TN-C protein as well as mRNA in a dose-dependent manner. Actinomycin D, an RNA synthesis inhibitor, significantly blocked the PDGF-mediated upregulation of TN-C mRNA expression, whereas cycloheximide, a protein synthesis inhibitor, did not. The PDGF-mediated induction of TN-C expression was inhibited by the treatment of fibroblasts with a selective phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, or LY294002. These results suggest that PDGF induced the expression of TN-C at a transcriptional level via phosphoinositide3-kinase/Akt signaling pathways. We performed serial 5' deletions and a transient transfection analysis to define the region in the TN-C promoter mediating the responsiveness to PDGF. Overexpression of Sp1, Ets1, or Ets2 activated the TN-C promoter and superinduced TN-C promoter activity stimulated by PDGF, whereas overexpression of Fli1 inhibited the effects of PDGF on TN-C expression. Mutation of the Sp1/3 binding sites or Ets binding sites in the TN-C promoter region responsible to PDGF abrogated the PDGF-inducible promoter activity. Immunoprecipitation analysis revealed that Sp1, Ets1, and Ets2 form a transcriptionally active complex. On the other hand, the interaction of Fli1 with Sp1 decreased after PDGF treatment. These results suggest that the upregulation of TN-C expression by PDGF involves Ets family transcription factors, co-operating with Sp1.

Base Sequence↗