Background: Systemic corticosteroids are one of the most commonly used therapeutic modalities for patients with extensive alopecia areata (AA), although they entail several drawbacks. Objective: To determine the best modality for systemic corticosteroid use in terms of their efficacy, relapse rate, and side effects. Methods: Fifty-one patients with single or multiple AA (AA/multiplex) and 38 patients with alopecia totalis or AA universalis (AA totalis/universalis) were enrolled in this open study. They were randomly divided into three groups depending on the time of their initial visit. They were administered (1) oral dexamethasone (Dex) 0.5 mg/day for 6 months (Dex group), (2) intramuscular triamcinolone acetonide (imTA) 40 mg once a month for 6 months followed by 40 mg once every 1.5 months for 1 year (imTA group), and (3) pulse therapy (PT) using oral predonine 80 mg for 3 consecutive days once every 3 months (PT group). After the treatment, each treatment modality was evaluated by the response rate, relapse rate, and side effect profile. Results: The response rate of AA/multiplex was significantly better in the imTA group than in the Dex group. The overall relapse rate and that of AA totalis/universalis were significantly better in the PT group than in the Dex group. Dysmenorrhea was the most common and problematic side effect. Impairment of the adrenocortical reserve was seen in 7% of the PT group and 23% of the imTA group, which was recov ered without any further medical treatment. Conclusion: imTA or pulse therapy is effective for AA and has an acceptable level of side effects. The development of a new strategy to reduce the relapse rate is needed.
There is growing evidence that diesel exhaust particles (DEP) can induce allergic diseases with increased IgE production and preferential activation of Th2 cells. To clarify the cellular basis of the role of DEP in the induction of Th2-dominant responses, we examined the effects of DEP on the cytokine production by T cells stimulated with anti-CD3/CD28 Ab and on that by monocyte-derived dendritic cells (MoDCs) stimulated with CD40L and/or IFN-γ. We examined IFN-γ, IL-4, IL-5, IL-8, and IL-10 produced by T cells and TNF-α, IL-1β, IL-10, and IL-12 produced by MoDCs using real-time PCR analysis or by ELISA. To highlight the effects of DEP, we compared the effects of DEP with those of dexamethasone (DEX) and cyclosporin A (CyA). DEP significantly suppressed IFN-γ mRNA expression and protein production, while it did not affect IL-4 or IL-5 mRNA expression or protein production. The suppressive effect on IFN-γ mRNA expression was more potent than that of DEX and comparable at 30 μg/ml with 10−7 M CyA. The suppressive effect on IFN-γ production was also more potent than that of either DEX or CyA. DEP suppressed IL-12p40 and IL-12p35 mRNA expression and IL-12p40 and IL-12p70 production by MoDCs, while it augmented IL-1β mRNA expression. Finally, by using a thiol antioxidant, N-acetyl cysteine, we found that the suppression of IFN-γ production by DEP-treated T cells was mediated by oxidative stress. These data revealed a unique characteristic of DEP, namely that they induce a Th2 cytokine milieu in both T cells and dendritic cells.
Treatment of human leukemia THP-1 cells with bufalin, a specific inhibitor of Na(+)-K(+)-ATPase, sequentially induces c-fos and inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) gene expressions before the appearance of mature phenotypes of monocytic cells. In this study we examined the signal transduction leading to bufalin-induced gene expressions. Bufalin selectively activated extracellular signal-regulated kinase (ERK), compared with other mitogen-activated protein (MAP) kinase family members. Pretreatment of THP-1 cells with PD-98059, an inhibitor of the ERK-kinase cascade, abolished bufalin-induced c-fos and IL-1 beta gene expressions, indicating that the ERK-kinase cascade mediates the induction of inflammatory cytokines by bufalin. Inhibition of the Na(+)/Ca(2+) exchanger by KB-R7943 and of protein kinase C (PKC) by Ro-31-8220 suppressed ERK activation and gene expressions of c-fos and IL-1 beta. These findings suggest that Na(+)-K(+)-ATPase inhibition by bufalin induces calcium influx and thereby activates PKC and ERK. In cells treated with an inhibitor of p38 MAP kinases, SB-203580, bufalin-mediated ERK activation became persistent and the induction of IL-1 beta and TNF-alpha expressions was significantly augmented. These results suggest that cross talk in bufalin-mediated ERK activation is negatively regulated by endogenous p38 MAP kinase activations.
Bufalin, an Na(+)-K(+)-ATPase inhibitor, simultaneously induced cell differentiation and apoptosis in human monocytic leukemia THP-1 cells. In this study, we investigated the regulatory role of protein kinase C (PKC) isozymes in bufalin-induced cell differentiation and apoptosis. A PKC-specific but isozyme-nonselective inhibitor, Ro-31-8220, and a cPKC selective inhibitor, Gö-6976, caused significant attenuation of bufalin-induced interleukin-1beta (IL-1beta) gene expression, a mature monocytic marker, indicating that cPKC participates in the bufalin-induced cell differentiation. On the other hand, cPKCbeta- and nPKCdelta-defective THP-1/TPA cells displayed strong resistance to the bufalin-induced DNA ladder formation. Rottlerin, an nPKCdelta-specific inhibitor, partially attenuated preapoptotic effects of bufalin, such as the limited proteolysis of nPKCdelta and poly(ADP-ribose) polymerase and the cell staining by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, suggesting that nPKCdelta is involved, at least in part, in bufalin-induced apoptosis. In contrast, Gö-6976 and rottlerin significantly augmented bufalin-induced apoptosis and differentiation, respectively. The findings suggest that bufalin-induced cell differentiation and apoptosis are interlinked and that distinct PKC isozymes are involved in the fate of the cell.
Ber-EP4 is an antibody to a cell membrane glycoprotein of unknown function. In the skin, Ber-EP4 immunoreactivity has been reported to be localized in structures composed of basaloid epithelial cells, i.e. fetal epithelial germ cells, basal cell carcinoma, and trichoepithelioma as well as eccrine or apocrine ducts. In this study, we further characterized the follicular expression of Ber-EP4 immunoreactivity at different stages of the hair cycle of human terminal hair follicles. In addition, to clarify the location of Ber-EP4(+) cells, we compared the Ber-EP4 immunoreactivity with the expression of keratin 15 and keratin 19. Positive staining by Ber-EP4 was found in the lower part of the epithelial strand of late catagen hair follicles, in the secondary hair germ of telogen hair follicles, and in the matrix of early anagen hair follicles but not in any parts of mature anagen hair follicles. In contrast, the follicular expression of keratin 15 detected by using LHK15 antibody was restricted to two distinct parts of anagen hair follicles, i.e. the outer root sheath above the hair bulb and that of the isthmus including the bulge area, and to the outer root sheath of late catagen and telogen hair follicles. The follicular expressions of keratin 19 and that of keratin 15 were apparently superimposed, whereas keratin 15 expression was more extended. The immunoreactivity of LHK15 antibody and antikeratin 19 antibody against the secondary hair germ of telogen follicles was negative or dim. Our results suggest that Ber-EP4 reacts with the secondary hair germ and possibly a cell population related to the secondary hair germ but not with the presumptive stem cell population as revealed immunohistochemically either by the keratin 15 or keratin 19 expression.
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