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Biomedical subjects

K Jimbow

Publications and source records attributed to K Jimbow.

At least 37 records · Page 2Linked to original sources
PubMed2000

Immunosuppressive effect on T cell activation by interleukin- 16-cDNA-transfected human squamous cell line.

It is well known that it is difficult to induce an immunotolerance with allogeneic skin transplantation. We attempted to find the immunosuppressive protocol for prolonging skin allograft rejection by using interleukin-16 because IL-16 is considered one of the natural ligands to CD4 molecules. First we examined whether synergistic immunosuppressive effects of recombinant IL-16 plus anti-CD4 mAbs are induced in mixed lymphocyte reaction (MLR). Next we used IL-16-cDNA-transfected OSC-20 (human oral squamous cell carcinoma cell line) as an in vitro model of the epidermal keratinocyte equivalent and examined whether this transfectant could inhibit the activation of allogeneic T cells. Our data indicated that IL-16 clearly inhibited human MLR and that IL-16 increased synergistically the immunosuppressive effect of anti-CD4 mAb. We also used IL-16 transfectant and this produced more than 50 ng/ml of IL-16 in the supernatant by which human MLR was significantly inhibited. Furthermore, this transfectant also inhibited the activation of allogeneic lymphocytes stimulated directly with transfectant cells. These results indicated that the IL-16-producing allogeneic skin graft might have a local immunosuppressive action that would prolong graft survival.

Antibodies, Monoclonal↗
PubMed2000

Downregulation of CXCR-2 but not CXCR-1 expression by human keratinocytes by UVB.

Interleukin-8 (IL-8) belongs to the CXC chemokine family. IL-8 exerts its biological activities by binding to specific cell surface receptors, CXCR-1 and CXCR-2. Both receptors bind IL-8 with high affinity but they have different affinities for MGSA/Groalpha and NAP-2. It has been shown that the expression of epidermal CXCR-2 is increased in psoriasis, suggesting that activation of KC mediated by CXCR-2 contributes to the characteristic epidermal changes observed in psoriasis. In order to examine the mechanism(s) by which UVB therapy is effective for several dermatoses including psoriasis, we sought to examine if UVB would modulate the expression of CXCR-1 and CXCR-2 in human keratinocytes (KC). Constitutive expression of CXCR-1 and CXCR-2 mRNA was detected by RT-PCR in normal cultured human KC. After 100 or 300 J/m(2) irradiation, a decrease in CXCR-2 mRNA was detectable from 12 h after irradiation; this downregulation was observed until 48 h after irradiation. In contrast, the CXCR-1 mRNA level was unchanged. Immunohistochemical studies and flow cytometry analysis confirmed the suppressive effect of UVB on the expression of CXCR-2 protein in cultured human keratinocytes. Immunohistochemical studies on two minimal erythema doses (2MED)-exposed and 2MED-unexposed skin from healthy volunteers revealed that CXCR-2 staining occurred over the whole layer of the epidermis but at 24 h after 2MED irradiation, the positive staining of CXCR-2 was decreased. A faint CXCR-1 staining was observed in the lower part of the epidermis both in unexposed and exposed skins. Our results indicate that UVB-induced growth inhibition of KC in hyperproliferative skin disorders may, in part, be related to downregulation of CXCR-2.

Antigens, CD↗
PubMed2000

Intracellular vesicular trafficking of tyrosinase gene family protein in eu- and pheomelanosome biogenesis.

The intracellular vesicular trafficking in the melanosome biogenesis (melanogenesis) is reviewed with the incorporation of our own experimental findings. The melanosome biogenesis involves four stages of melanosome maturation, which reflect the transport of structural and enzymatic proteins from Golgi (trans-Golgi network: TGN) to the melanosomal compartment and their organization therein. The major melanosomal proteins include tyrosinase gene family protein (tyrosinase and tyrosinase-related protein; TRP), lysosome-associated membrane protein (Lamp) and gp100 (pmel 17). They are glycosylated in the endoplasmic reticulum, and transported by vesicles from the TGN to the melanosomal compartment. During the formation of transport vesicles, they assemble on the cytoplasmic face of the TGN to select cargo by interacting directly or indirectly with coat proteins. Tyrosinase and TRP-1 possess the dileucine motifs at the cytoplasmic domain, to which adapter protein-3 binds to transport them from the TGN to stage I melanosomes (related to late endosomes) and then to stage II melanosomes. A number of small guanosine triphosphate-binding proteins, including rab 7, appear to be involved in this vesicular transport. Phosphatidyl inositol 3 kinase also regulates this membrane trafficking of melanosomal glycoprotein. Eumelanogenesis is controlled by melanocyte-stimulating hormone, and all three tyrosinase gene family proteins are transported from the TGN to stage II melanosomes that are elliposoidal and contain the structural matrix of filaments/lamellae. In contrast, pheomelanogenesis is primarily regulated by agouti signal protein, and only tyrosinase is transported from stage I melanosomes to stage II melanosomes that are spherical and related to lysosomes. Because of the absence of TRP-1 and TRP-2 in pheomelanogenesis, it may be suggested that tyrosinase is involved in lysosomal degradation after forming dopaquinone, to which the cysteine present in the lysosomal granule binds to form cysteinyldopas that will then be auto-oxidized to become pheomelanin.

Animals↗
PubMed2000

Assembly, target-signaling and intracellular transport of tyrosinase gene family proteins in the initial stage of melanosome biogenesis.

Assembly, target-signaling and transport of tyrosinase gene family proteins at the initial stage of melanosome biogenesis are reviewed based on our own discoveries. Melanosome biogenesis involves four stages of maturation with distinct morphological and biochemical characteristics that reflect distinct processes of the biosynthesis of structural and enzymatic proteins, subsequent structural organization and melanin deposition occurring in these particular cellular compartments. The melanosomes share many common biological properties with the lysosomes. The stage I melanosomes appear to be linked to the late endosomes. Most of melanosomal proteins are glycoproteins that should be folded or assembled correctly in the ER through interaction with calnexin, a chaperone associated with melanogenesis. These melanosomal glycoproteins are then accumulated in the trans Golgi network (TGN) and transported to the melanosomal compartment. During the formation of transport vesicles, coat proteins assemble on the cytoplasmic face of TGN to select their cargos by interacting directly or indirectly with melanosomal glycoproteins to be transported. Adapter protein-3 (AP-3) is important for intracellular transport of tyrosinase gene family proteins from TGN to melanosomes. Tyrosinase gene family proteins possess a di-leucine motif in their cytoplasmic tail, to which AP-3 appears to bind. Thus, the initial cascade of melanosome biogenesis is regulated by several factors including: 1) glycosylation of tyrosinase gene family proteins and their correct folding and assembly within ER and Golgi, and 2) supply of specific signals necessary for intracellular transport of these glycoproteins by vesicles from Golgi to melanosomes.

Amino Acid Sequence↗
PubMed2000

Development of squamous cell carcinoma by two high-risk human papillomaviruses (HPVs), a novel HPV-67 and HPV-31 from bowenoid papulosis.

We report a patient with bowenoid papulosis (BP) involving two high-risk human papillomaviruses (HPVs) and the development of invasive squamous cell carcinoma (SCC). Our patient showed verrucous lesions on the penis, perianal area and groin that had been noted over the previous 8 years and had recurred after all therapeutic approaches. The perianal and left inguinal lesions revealed invasive SCC on histology. HPV-31 and HPV-67 sequences were detected by polymerase chain reaction from BP lesions of the perianal area and the shaft of the penis. HPV-31 has already been reported in BP as a high-risk HPV for the development of SCC, but HPV-67 is a novel one that has never been reported in BP. As HPV-67 has sequence homology to HPV-52 and HPV-58, it belongs to the family of HPV-16, a high-risk HPV group. Thus our patient showed two high-risk HPVs, i.e. HPV-31 and the novel HPV-67, which may be directly involved in the development of SCC.

Adult↗
PubMed2000

UVB photosensitivity due to ranitidine.

We describe a 62-year-old male with photosensitivity due to ranitidine. An oral challenge test after taking ranitidine with UVB irradiation was positive. Ranitidine-induced UVB photosensitivity was persistent even after cessation of the medication.

Dermatitis, Photoallergic↗
PubMed2000

Malignant melanoma in a patient with oculocutaneous albinism.

BACKGROUND: Sun-induced malignancies (basal cell and squamous cell carcinomas) are common in oculocutaneous albinism, however, the incidence of malignant melanoma is a topic of controversy. OBJECTIVE: We have reviewed the literature and report a case of a woman with oculocutaneous albinism with an amelanotic melanoma of the anterior chest wall. RESULTS: There are only 26 previously reported cases (both case reports and African albino population studies) in 25 patients in the literature. A 27th case with immunohistochemical and ultrastructural evaluation is presented. CONCLUSIONS: It appears that melanoma, a malignancy for which sun exposure and light colouration are felt to be major risk factors, has a low incidence among a population that is both hypopigmented and often exposed to high levels of ultraviolet light. This low incidence is poorly understood and frequently disputed.

Albinism, Oculocutaneous↗
PubMed2000

Comparison of in vitro cytotoxicity of N-acetyl and N-propionyl derivatives of phenolic thioether amines in melanoma and neuroblastoma cells and the relationship to tyrosinase and tyrosine hydroxylase enzyme activity.

Our laboratory has synthesized two new phenolic thioether amines, N-propionyl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) and N[2-[(4-propionyloxyphenyl)thio]ethyl] propionamide (N,O-diPr-4-S-CAP). These compounds, along with the previously described phenolic thioether amine N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) and its acetyl form (N,O-diAc-4-S-CAP), are tyrosine-amine derivative analogues. The cytotoxicity of these compounds is thought to be tyrosinase dependent, which may make them suitable for targeted anti-melanoma therapy since only melanocytes and their malignant counterparts contain this active enzyme. To further investigate this hypothesis, we performed MTT [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide] assays to determine the cytotoxicity of these compounds in 10 different cell lines. Specifically, we examined to what extent cytotoxicity is related to tyrosinase and tyrosine hydroxylase activity using melanoma and neuroblastoma cells, which have a common metabolic pathway using tyrosinase and tyrosine hydroxylase, respectively. The most sensitive cell line was the highly pigmented SK-MEL-23 melanoma cell line, which shows a very high tyrosinase activity with the highest melanin pigmentation. KAN and SK-NSH (two neuroblastoma cell lines), which have no tyrosinase activity but high tyrosine hydroxylase, were also sensitive. However, C32 (a non-pigmented melanoma with a lower tyrosinase activity) was also sensitive, and MeWo (a moderately pigmented melanoma with a high tyrosinase activity) was less sensitive. This in vitro study may indicate that there is a non-tyrosinase-mediated mechanism of cytotoxicity for phenolic thioether amines in addition to the tyrosinase-mediated one described previously.

Amides↗
PubMed1999

Sulfur containing tyrosine analogs can cause selective melanocytotoxicity involving tyrosinase-mediated apoptosis.

Sulfur-containing tyrosine analogs such as 4-S-cysteaminylphenol (4-S-CAP) and its N-acetyl derivative, N-acetyl-4-S-CAP, are tyrosinase substrates and can cause selective cytotoxicity or cell death of melanocytes and melanoma cells. It is not clear, however, if the cytotoxicity derives from a cytostatic or cytocidal effect. The latter can also be either apoptotic or necrotic. This paper summarizes our attempt to clarify the nature of melanocytotoxicity and cell death by using a new derivative of 4-S-CAP, N-propionyl-4-S-CAP (NPr-CAP). The i.p. administration of NPr-CAP caused marked depigmentation of black hair follicles in C57 mice. At 12 h postadministration of NPr-CAP, follicular melanocytes showed histochemical and morphologic features indicative of apoptosis by TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining and electron microscopy. The agarose gel electrophoresis of DNA from drug-treated melan a2 cells, an immortal melanocyte line of C57 black mice, showed the nucleosomal DNA ladder pattern. NPr-CAP caused irreversible cytotoxicity in melan a2 and the effect was inhibited by a tyrosinase inhibitor, phenylthiocarbamide. The tyrosinase-mediated cytotoxicity of NPr-CAP was further confirmed by the decreased viability of COS 7 monkey-kidney cells, which expressed a level of high tyrosinase activity through transfection of human tyrosinase cDNA. NPr-CAP, however, also transiently inhibited the proliferation of melan c cells, a control tyrosinase-negative albino melanocyte line, and vector-transfected COS 7 cells. Thus, the major process of NPr-CAP-mediated melanocytotoxicity involves cytocidal apoptosis associated with active tyrosinase. In addition, there is transient, nontyrosinase-mediated cytostatic cytotoxicity.

Animals↗
PubMed1999

Selective incorporation and specific cytocidal effect as the cellular basis for the antimelanoma action of sulphur containing tyrosine analogs.

Tyrosine analogs are good candidates for developing melanoma chemotherapy because melanogenesis is inherently toxic and uniquely expressed in melanocytic cells. Sulphur containing substrate (tyrosine) analogs, N-acetyl-4-S-cysteaminylphenol (NAcCAP) and N-propionyl-4-S-cysteaminylphenol (NPrCAP), have been shown to have potent antimelanoma activity in mice bearing melanoma. Both NAcCAP and NPrCAP show selective cytotoxicity towards melanoma cell lines. But the mechanism leading to selectivity is not clear as these drugs are also toxic to other cell lines to a lesser extent. Here we show that these drugs have both cytostatic and cytocidal effects, which could account for this. Cytostatic effect is suggested by DNA flow cytometry. The drug causes cell cycle changes in four human cell lines (normal skin fibroblasts, HeLa cells, and melanoma cell lines, C32 and SK-MEL-23) in a dose-dependent manner blocking cells in S phase with concomitant decrease in the number of cells in G1 phase. There is also a gradual decrease in cells in G2 + M phases. The dose-concentration curves give IC50 values in the range of 50-400 microM and the melanotic melanoma cell line SK-MEL-23 has the lowest IC50 value consistent with our hypothesis that these drugs are selective towards melanoma cells. The concentration-dependent accumulation of cells in S phase suggest a cytostatic effect as a consequence of inhibition of DNA synthesis in agreement with [3H] thymidine incorporation assay. There is a highly specific uptake of [14C]NAcCAP and irreversible damage to DNA synthesis machinery in SK-MEL-23 cells, indicating a melanotic-specific cytocidal effect as well. Trypan blue exclusion study and competitive inhibition assay indicated that visible cytocidal effect occurs slowly and oxidative stress resulting from tyrosinase mediated oxidation of the drug appears to be the underlying mechanism. The primary antimelanoma effect of cysteaminylphenols derives from a selective cytostatic effect, but is followed by a specific cytocidal action rendering the drugs useful for targeted melanoma chemotherapy.

Animals↗
PubMed1999

Promotion of tyrosinase folding in COS 7 cells by calnexin.

To understand the process of expression of tyrosinase, a key enzyme of melanogenesis, we examined its maturation in the endoplasmic reticulum (ER) by using a heterogeneous expression system. When human tyrosinase cDNA was introduced into COS 7 cells, tyrosinase activity was minimally detected. Immunofluorescence study revealed that tyrosinase was immunolocalized in the nuclear rim, the reticular network, and the punctuated structures. Because a cytoplasmic tail of tyrosinase-gene family protein functions as a lysosomal targeting signal in non-melanocytic cells, and immature and/or misfolded molecules are selectively retained in the ER, the observed localization suggested the inefficient maturation in the COS 7 cells. We thus examined if supplementation of calnexin, a membrane-bound chaperone with affinity for oligosaccharide-processing intermediates containing monoglucose, could improve the process. As expected, the activity was enhanced approximately 2-fold by co-transfection of cDNA encoding calnexin. In contrast, co-transfection of the cytosolic tail-free calnexin, which inhibits calnexin function by allowing premature egress of its ligands from the ER, suppressed expression of this enhanced tyrosinase activity. When alpha-glucosidase activity, which is required for calnexin function, was inhibited by castanospermine (CST) treatment, expression of tyrosinase activity was completely abolished. To confirm the direct involvement of calnexin in tyrosinase maturation, the interaction of calnexin with tyrosinase was examined. Immunoprecipitation of calnexin from extracts of [35S]methionine labeled cells with anti-calnexin antibody revealed that the association is highest immediately after the pulse and that nascent tyrosinase is gradually dissociated upon chase. The association was completely inhibited when CST was included in the medium. Hence, we suggest that the proper folding of tyrosinase is largely dependent on its direct interaction with calnexin for the determined duration in the ER.

Animals↗
PubMed1998

Synthesis and antitumour effect of the melanogenesis-based antimelanoma agent N-propionyl-4-S-cysteaminylphenol.

Chemotherapy of malignant melanoma is still a great challenge, as no effective drugs are available. The development of melanogenesis-based drugs is a promising area of research because melanogenesis is a unique biochemical pathway operating only in melanoma cells (and their normal counterparts) so that the tumour can be targeted. We have been using cysteinylphenol, a sulphur-containing analogue of tyrosine, and derivatives for that purpose. N-Acetyl-4-S-cysteaminylphenol was found to have the best antimelanoma effect in cell culture systems and in mice bearing B16 melanoma tumours. It also caused depigmentation of the skin, suggesting the possibility of use as a hypopigmenting agent. To improve the efficiency of the drug, we thought of replacing the acetyl group in N-acetyl-4-S-cysteaminylphenol with a propionyl group in the hope that increased hydrophobicity would increase the cellular uptake of the drug. N-Propionyl-4-S-cysteaminylphenol was synthesized by condensing 4-hydroxythiophenol with 2-ethyl-2-oxazoline. The drug showed both cytostatic and cytocidal effects in a human melanotic melanoma cell line. The drug was found to be a good depigmenting agent for the black hair follicles of C57 black mice when given s.c. for 14 days. A 10-day treatment with N-propionyl-4-S-cysteaminylphenol at 300 mg/kg body weight reduced the growth rate of B16 melanoma s.c. tumours in mice by 36%. The propionyl derivative was found to increase the life span of mice bearing melanoma more effectively than did the acetyl derivative.

Animals↗
PubMed1998

Dose-dependent induction of IL-12 but not IL-10 from human keratinocytes after exposure to ultraviolet light A.

Ultraviolet light A (UVA) is shown to play an augmentative or synergistic role with UVB in pathophysiological conditions induced by solar radiation. Thus, UVA would contribute significantly to the development of skin malignancies. It remains unclear, however, how UVA contributes to solar radiation-induced immune suppression. Keratinocytes (KC) produce cytokines which are a significant mediator of inflammatory and immunologic reactions in skin exposed to solar radiation and are a potent mediator in the induction of immune suppression. To examine if UVA alters the expression and production of cytokines from KC, normal human keratinocytes (HuSK) were cultured and exposed to UVA at doses ranging between 2.5 and 20 kJ/m2. Constitutive expression of the p35 subunit of interleukin (IL)-12 was detected by reverse transcription-polymerase chain reaction (RT-PCR) and the p40 subunit was induced by UVA irradiation dose dependently. IL-12 protein was also detected in the supernatants from UVA-irradiated HuSK by enzyme-linked imuunosorbent assay (ELISA) and confirmed by a bioassay. On the other hand, the same doses of UVA did not induce IL-10 mRNA or IL-10 protein which has been shown to be one of the cytokines responsible for the induction of UVB-induced immunosuppression. Considering that IL-12 promotes activation of Th1 cells and prevents the activation of Th2 cells and that administration of IL-12 has been shown to block the induction of immune suppression in UV-irradiated animals, our results suggest that UVA modulates skin immune function distinctively from UVB by affecting the balance between IL-10 and IL-12 produced from KC.

Cells, Cultured↗
PubMed1998

Vitiligo. Therapeutic advances.

Vitiligo often induces severe cosmetic disfigurement in patients. Both nonsurgical (medical) and surgical approaches for repigmenting vitiliginous macules are described (Table 1). Currently PUVA therapy appears to be the best method in providing reasonable hope for achieving repigmentation. Guidelines for both topical and systemic PUVA are available. Furthermore, surgical graft of autologous epidermal sheet or cultured melanocytes (often combined with keratinocyte co-culture) can be introduced to repigment the depigmented areas where PUVA is ineffective. PUVA therapy after autologous skin graft can enhance the repigmenting efficiency. Although PUVA with or without surgical procedure represents a useful tool in vitiligo treatment, we should look for other new treatment modalities based upon better understanding of basic biology of melanin pigmentation and pathophysiology of this disease. A recent development of topical pseudocatalase and calcium application combined with UVB phototherapy may be one of the typical examples in this respect. Many patients are significantly affected psychologically by the disease. Physicians should attempt to assess the degree of psychological impairment caused by vitiligo. Supportive care should always be offered if necessary in order to minimize these problems appropriately. In closing, normal skin of vitiligo patients can be totally depigmented by monobenzyl ether of hydroquinone in order to match the skin color in certain generalized vitiligo patients. There is a recent case report of extensive vitiligo with rapid repigmentation of depigmenting vitiliginous skin within a few weeks after discontinuing successful depigmentation therapy by monobenzyl ether of hydroquinone.

Adrenal Cortex Hormones↗
PubMed1998

Functional regulation of tyrosinase and LAMP gene family of melanogenesis and cell death in immortal murine melanocytes after repeated exposure to ultraviolet B.

This study characterizes the induction of melanogenesis and the expression of tyrosinase, tyrosinase-related protein (TRP) and lysosome-associated membrane protein (LAMP) gene families in the cultured melanocyte lines of non-agouti mice with four major genetic loci, i.e. melan-a2 (black, wild type), melan-b (brown, TRP-1 mutation), melan-s (black, piebaldism mutation) and melan-c (white, tyrosinase mutation) in response to repeated exposure to ultraviolet (UV) B (5 mJ/cm2, 7 consecutive days). Electron microscopy showed that new melanogenesis was induced in melan-a2, melan-s and melan-b melanocytes. Melan-a2, melan-s and melan-b showed an almost twofold increase in tyrosinase activity and gene expression with increased synthesis of melanosomes, although melan-b showed a minimum increase in tyrosinase activity. There was a twofold upregulation of LAMP-1 mRNA but no alteration in LAMP-2 and LAMP-3 mRNA expression in melan-a2, while there was no alteration in LAMP-1 mRNA expression but increased expression of LAMP-2 and LAMP-3 mRNA in melan-s, LAMP-3 showing a higher increase. Melan-b cells showed the same gene expression of LAMP-1, LAMP-2 and LAMP-3 as that of non-UV exposed cells. All three lines, however, exhibited simultaneously cell death, melan-b reaching the highest rate of cell death (96.5%). In contrast, melan-c, which did not have any tyrosinase activity with failure of melanogenesis induction, expressed all the mRNAs of the tyrosinase and LAMP gene families, but was not associated with any significant melanocyte death. Our study indicated: (i) that melanogenesis induction and melanocyte death are two photobiological processes occurring simultaneously after repeated UVB exposure, (ii) that in response to an upregulation of tyrosinase mRNA and enzymic activity, there was a co-ordinated upregulation of the LAMP-1 gene in wild type melan-a2, while no upregulation was found in melan-s and melan-b mutants, and (iii) that UV-induced melanocyte death is related to the upregulation of the tyrosinase gene, induction of new melanogenesis and mutation of the TRP-1 gene in immortal murine melanocytes.

Animals↗