Body mass index, HbA1c and serum C-reactive protein are predictors of secondary failure in infliximab continuance for Japanese psoriasis patients: A hospital-based retrospective case-control study.

Biologics has had a great impact on psoriasis treatment as well as the life of psoriasis patients. Infliximab (IFX), one of the biologics targeting tumor necrosis factor (TNF), is the first of the biologics introduced to Japanese psoriasis patients. Many patients had benefits of IFX from initial applications and sustained remission of skin lesions and arthritis. Some, however, fall into so-called secondary failure, in which patients become less responsive to IFX when the treatment is repeated. The mechanism of secondary failure and the background of patients with secondary failure have not been completely elucidated. To address this issue, we retrospectively evaluated psoriasis patients treated with IFX in our department. In this retrospective, single-center, case-control study based on the clinical record, a total of 34 patients were enrolled. We excluded 7 patients who discontinued IFX because of adverse events of IFX. We divided other 27 patients into two groups; 16 patients who kept using IFX (Continuance group); and 11 patients who switched to other treatments (Discontinuance group). Among various clinical features, body mass index (BMI), HbA1c, and serum CRP level were significantly higher in the Discontinuance group than the Continuance group. The results indicated that these three clinical features of BMI, HbA1c and serum CRP level before treatment are the predictors of successful IFX treatment and suggest that improvement of metabolic conditions contributes to avoiding secondary failure and discontinuance of IFX.

Oxidation of cell surface thiol groups by contact sensitizers triggers the maturation of dendritic cells.

p38 mitogen-activated protein kinase (MAPK) has a crucial role in the maturation of dendritic cells (DCs) by sensitizers. Recently, it has been reported that the oxidation of cell surface thiols by an exogenous impermeant thiol oxidizer can phosphorylate p38 MAPK. In this study, we examined whether sensitizers oxidize cell surface thiols of monocyte-derived DCs (MoDCs). When cell surface thiols were quantified by flow cytometry using Alexa fluor maleimide, all the sensitizers that we examined decreased cell surface thiols on MoDCs. To examine the effects of decreased cell surface thiols by sensitizers on DC maturation, we analyzed the effects of an impermeant thiol oxidizer, o-phenanthroline copper complex (CuPhen). The treatment of MoDCs with CuPhen decreased cell surface thiols, phosphorylated p38 MAPK, and induced MoDC maturation, that is, the augmentation of CD83, CD86, HLA-DR, and IL-8 mRNA, as well as the downregulation of aquaporin-3 mRNA. The augmentation of CD86 was significantly suppressed when MoDCs were pretreated with N-acetyl-L-cystein or treated with SB203580. Finally, we showed that epicutaneous application of 2,4-dinitrochlorobenzene on mouse skin significantly decreased cell surface thiols of Langerhans cells in vivo. These data suggest that the oxidation of cell surface thiols has some role in triggering DC maturation by sensitizers.

TGF-beta1 dampens the susceptibility of dendritic cells to environmental stimulation, leading to the requirement for danger signals for activation.

In contrast to its favourable effects on Langerhans cell (LC) differentiation, transforming growth factor (TGF)-beta1 has been reported to prevent dendritic cells from maturing in response to tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, or lipopolysaccharide (LPS). We first characterized the effects of TGF-beta1 on dendritic cell function by testing the response of TGF-beta1-treated monocyte-derived dendritic cells (MoDCs) to maturation stimuli that LCs receive in the epidermis, namely, haptens, ATP and ultraviolet (UV). TGF-beta1 treatment, which augmented E-cadherin and down-regulated dendritic cell-specific ICAM3-grabbing non-integrin on MoDCs, significantly suppressed their CD86 expression and hapten-induced expression of IL-1beta and TNF-alpha mRNA and protein. As TGF-beta1-treated MoDCs lacked Langerin expression, we demonstrated the suppressive effects of TGF-beta1 on haematopoietic progenitor cell-derived dendritic cells expressing both CD1a and Langerin. These suppressive effects of TGF-beta1 increased with the duration of treatment. Furthermore, TGF-beta1-treated MoDCs became resistant to apoptosis/necrosis induced by high hapten, ATP or UV doses. This was mainly attributable to dampened activation of p38 mitogen-activated protein kinase (MAPK) in TGF-beta1-treated MoDCs. Notably, although ATP or hapten alone could only induce CD86 expression weakly and could not augment the allogeneic T-cell stimulatory function of TGF-beta1-treated MoDCs, ATP and hapten synergized to stimulate these phenotypic and functional changes. Similarly, 2,4-dinitro, 1-chlorobenzene (DNCB) augmented the maturation of TGF-beta1-treated MoDCs upon co-culture with a keratinocyte cell line, in which ATP released by the hapten-stimulated keratinocytes synergized with the hapten to induce their maturation. These data may suggest that TGF-beta1 protects LCs from being overactivated by harmless environmental stimulation, while maintaining their ability to become activated in response to danger signals released by keratinocytes.

Increased hyaluronan production and decreased E-cadherin expression by cytokine-stimulated keratinocytes lead to spongiosis formation.

The pathogenesis of spongiosis, which is a well-known hallmark of acute eczema, is not fully understood. We sought to clarify the mechanism for the influx of tissue fluid into the epidermis and the loss of cohesion between keratinocytes in acute eczema that result in spongiosis. We first demonstrated increased intercellular accumulation of hyaluronan (HA) in the spongiotic epidermis by immunochemical staining using hyaluronic-acid-binding protein (HABP) and augmented hyaluronan synthase 3 (HAS3) mRNA expression by spongiotic keratinocytes using in situ hybridization. We also showed that the epidermis where the intercellular space was strongly stained with HABP showed weaker expression of membrane E-cadherin. Next, we demonstrated--by a sandwich assay using HABP, real-time PCR, and flow cytometry--that, among various cytokines, only IL-4, IL-13, and IFN-gamma increased HA production, enhanced HAS3 mRNA expression, and decreased membrane E-cadherin expression by normal human epidermal keratinocytes in both low- and high-Ca media. Finally, we demonstrated IL-4, IL-13, their combination, and IFN-gamma could induce intercellular space widening of the epidermis with increased HA accumulation and decreased E-cadherin expression in the organotypic culture. These results suggest that the augmented production of HA and the decreased E-cadherin expression by keratinocytes stimulated with IL-4/IL-13 or IFN-gamma cause spongiosis in acute eczema.

Molecular events in human T cells treated with diesel exhaust particles or formaldehyde that underlie their diminished interferon-gamma and interleukin-10 production.

BACKGROUND: A series of epidemiological and experimental studies have suggested that diesel exhaust particles (DEP) and formaldehyde (FA) may help trigger T helper type 2 (Th2)-mediated allergic responses. METHODS: To identify the molecular events by which DEP and FA induce a Th2-skewed immune response, we stimulated T cells from healthy subjects with anti-CD3/anti-CD28 monoclonal antibodies and examined the effect of pretreatment with DEP or FA on mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-kappaB by Western blotting and colorimetric NF-kappaB assays. We also examined the mRNA expression profiles of the T cells by microarray and real-time PCR analyses. RESULTS: FA selectively suppressed interferon (IFN)-gamma and interleukin-10 mRNA expression and protein production in stimulated T cells, as we previously reported with DEP. In the present study, we found that both DEP and FA suppressed NF-kappaB signaling and activated MAPKs. Both also significantly suppressed the mRNA expression of T-bet, Txk and c-Maf. Microarrays revealed significant augmentation of the expression of 2 FoxO3a-dependent genes, namely glucocorticoid-induced leucine zipper and growth arrest and DNA damage-inducible gene 45 alpha (Gadd45a), which are known to modulate T cell immune responses. Treatment with N-acetylcysteine reversed the augmented Gadd45a mRNA response and caused the suppressed IFN-gamma mRNA response to recover. CONCLUSIONS: DEP and FA have similar transcriptional and nontranscriptional effects on T cell signaling that together promote a Th2-skewed immune response.

Cadexomer as well as cadexomer iodine induces the production of proinflammatory cytokines and vascular endothelial growth factor by human macrophages.

Although cadexomer iodine is widely used for the treatment of skin ulcers such as decubitus ulcers, the mechanism by which it enhances wound healing is not clear. Recently, it has been demonstrated that macrophages play an important role in wound healing by inducing inflammation and angiogenesis. We examined the effects of cadexomer and cadexomer iodine on tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-8, IL-10, IL-12 p 40, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) production by macrophages. Human macrophages were obtained by culturing CD14+ monocytes with macrophage colony stimulating factor (M-CSF) in the presence or absence of cadexomer or cadexomer iodine. The production of cytokines and the expression of mRNA were evaluated by enzyme linked immunosorbent assay (ELISA) of the culture supernatants and by reverse transcriptase polymerase chain reaction (RT-PCR) analysis, respectively. In addition, we examined the tissue concentration of VEGF in the wounds treated with or without cadexomer iodine. Cadexomer and cadexomer iodine significantly increased the expression of IL-1 beta, IL-8, TNF-alpha and VEGF mRNA, while they did not affect that of IL-6, IL-10, IL-12 p 40 or bFGF mRNA. In addition, they significantly increased the production of IL-1 beta and TNF-alpha. Although we could not detect increased production of VEGF in the culture supernatants, the western blot analysis of macrophages demonstrated the increased production of VEGF by the treatment with either cadexomer or cadexomer iodine. The treatment with cadexomer iodine increased the tissue concentration of VEGF in the skin wounds. These data suggest that cadexomer and cadexomer iodine have beneficial effects on wound healing in addition to those related to their antibacterial activity.

Inhibitory effect of the polyinosinic-polycytidylic acid/cationic liposome on the progression of murine B16F10 melanoma.

Cellular proteins, retinoic acid inducible gene-I and Toll-like receptor 3, sense dsRNA including polyinosinic-polycytidylic acid (PIC) to stimulate innate immune response. The local administration of PIC has been demonstrated to be effective in anti-tumor immunotherapy. However, the effects of PIC delivered cross the cell membrane have not yet been examined. To address this issue, we used a complex of PIC and cationic liposome (PIC liposome) and examined its anti-tumor effects in vitro and in vivo. PIC liposome could directly suppress the growth of B16F10 melanoma in vitro and repeated peritumoral injections of PIC liposome inhibited melanoma growth in a dose-dependent manner. This treatment induced tyrosinase-related protein-2 (TRP-2)-tetramer(+) CD8(+) cells in the lymph nodes. As the mechanism for its anti-tumor immune response, we showed that the intradermal injection of PIC liposome induced the maturation of dendritic cells (DC). Moreover, the intratumoral injection of immature DC after treatment with PIC liposome significantly increased the number of TRP-2-specific IFN-gamma-producing cells in the lymph nodes as well as spleen, which resulted in an augmentation of the anti-tumor immune response. These studies demonstrate the potential of peritumoral injection of PIC liposome as immunotherapy for malignant melanoma.

Redox imbalance induced by contact sensitizers triggers the maturation of dendritic cells.

Although p38 mitogen-activated protein kinases (MAPK) play a crucial role in the activation of monocyte-derived dendritic cells (MoDC) by contact sensitizers, the upstream signals of p38 MAPK remain undetermined. To examine whether sensitizers induce redox or oxidative stress in dendritic cells (DC), which subsequently stimulate p38 MAPK, we measured the ratio of the oxidized (GSSG) versus reduced (GSH) form of cellular glutathione in MoDC stimulated with five sensitizers including NiCl2 and 2,4-dinitrochlorobenzene (DNCB) and three non-sensitizers including sodium dodecyl sulfate using colorimetric assays. All the sensitizers, but none of the non-sensitizers at sublethal concentration, reduced the GSH/GSSG ratio, which was accompanied by phosphorylation of p38 MAPK. Treatment with the antioxidant, N-acetyl-L-cysteine, which suppressed the reduction of the GSH/GSSG ratio, abrogated both the phosphorylation of p38 MAPK and the augmentation of CD86 expression. A similar response pattern was observed in THP-1 macrophage-monocyte cells. Unexpectedly, however, formaldehyde (HCHO) reduced the GSH/GSSG ratio in MoDC, but not in THP-1. This finding, in conjunction with the observation that DNCB and NiCl2 reduced the GSH/GSSG ratio at different kinetics, indicated that the sensitizers reduced the GSH/GSSG ratio by a different mechanism. These data suggest that the GSH/GSSG imbalance plays a crucial role in triggering DC maturation by sensitizers.

Cellular basis of the role of diesel exhaust particles in inducing Th2-dominant response.

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-gamma. We examined IFN-gamma, IL-4, IL-5, IL-8, and IL-10 produced by T cells and TNF-alpha, IL-1beta, 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-gamma 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-gamma mRNA expression was more potent than that of DEX and comparable at 30 mug/ml with 10(-7) M CyA. The suppressive effect on IFN-gamma 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-1beta mRNA expression. Finally, by using a thiol antioxidant, N-acetyl cysteine, we found that the suppression of IFN-gamma 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.

Indolent herpetic whitlow of the toe in an elderly patient with diabetic neuropathy.

We report a case of indolent herpetic whitlow of the toe occurring in an elderly male patient with poorly controlled diabetes mellitus. In this case, the mechanism of transmission was not clear, although he was in a habit of taking a hot spring bath. This patient's symptoms were unusual for herpes simplex; he had no pain in the presence of diabetic neuropathy. The standard therapeutic dose of acyclovir was not effective in suppressing the lesions, and a higher dose was required to induce complete healing.

p38 Mitogen-Activated protein kinase mediates dual role of ultraviolet B radiation in induction of maturation and apoptosis of monocyte-derived dendritic cells.

Although ultraviolet B (UVB) induces apoptosis and functional perturbations in dendritic cells (DC), for example, Langerhans cells (LC), it also stimulates some LC into maturation after irradiation in vivo. To analyze its reciprocal effects on DC, we elucidated the direct effect of UVB on DC in vitro using human monocyte-derived DC (MoDC). UVB from 50 to 200 J per m2 stimulated the maturation of MoDC with (1) augmented expression of CD86 and HLA-DR, (2) enhanced production of IL-1beta, IL-6, IL-8, and TNF-alpha at both the mRNA and protein levels, and (3) enhanced allostimulatory capacity on a per-cell basis, whereas the exceeded doses induced apoptotic cell death. Western-blot analysis of MoDC after UVB demonstrated a concentration-dependent phosphorylation of p38- and c-JUN N-terminal kinase (JNK)-mitogen-activated protein kinases (MAPK), but not that of extracellular signal-regulated kinases. p38 MAPK-inhibitor, SB203580, inhibited both UVB-induced maturation and apoptosis of MoDC. Interestingly, MoDC that had undergone apoptosis exhibited an augmented expression of HLA-DR without upregulation of CD86 antigen, suggesting their tolerogenic phenotype. Thus, our study revealed a dual effect of UVB, to stimulate maturation or to induce apoptosis in MoDC, depending on the dosage, via p38 MAPK pathway.

Interleukin-3 in cooperation with transforming growth factor beta induces granulocyte macrophage colony stimulating factor independent differentiation of human CD34+ hematopoietic progenitor cells into dendritic cells with features of Langerhans cells.

Recently, we have reported that M-CSF in cooperation with TGF-beta1 can induce Langerhans cell (LC) development from hematopoietic progenitor cells (HPCs) without GM-CSF. In the present study, we examined whether TGF-beta1 changes the differentiation of HPCs induced by IL-3 towards LC development. We cultured HPCs in a serum-free medium in the presence of IL-3 and a combination cytokines including Flt3L, SCF, and TNF-alpha with or without TGF-beta1. DCs induced by the IL-3 culture (IL-3 DCs) did not significantly differ from those induced by the GM-CSF culture (GM-CSF DCs). Namely, both expressed CDla, F-cadherin, and Langerin in the presence of TGF-beta1 and stimulated allogeneic T cells at a similar magnitude. In contrast to GM-CSF DCs, IL-3 DCs lacked the expression of Birbeck granules (BGs) in spite of their expression of Langerin. When we compared the expression of Langerin between these two DCs, however, it became clear that both Langerin protein and mRNA were significantly lower in IL-3 DCs than in GM-CSF DCs. These studies again demonstrated the ability of TGF-beta1 to polarize the differentiation of HPCs induced by IL-3 towards LC development, although IL-3 DCs were unable to form BGs partly because of their poor ability to induce Langerin.

Resolution of a leg ulcer after hysterectomy for huge uterine myoma.

Venous ulcers are the most common type of leg ulcers, accounting for 80% to 90% of cases. We report a large, therapy-resistant ulcer present for three months on the right leg of a 44-year-old woman who also had a huge uterine myoma. Without any other treatment, the leg ulcer regressed spontaneously three months after a hysterectomy for the uterine myoma that had been demonstrated in a CT image to be compressing the right common iliac vein in the pelvis. Uterine myoma can become the cause of venous insufficiency of the leg, when it is big enough to disturb the blood circulation in the pelvis in individuals who have incompetent perforating veins.

Evaluation of the efficacy of antihistamines using human monocyte-derived dendritic cells stimulated with histamine.

BACKGROUND: It has been reported that histamine induces CD86 expression and chemokine production in human immature monocyte-derived dendritic cells (MoDCs), which can be blocked by both H(1)- and H(2)-receptor antagonists. OBJECTIVE: We sought to examine whether the efficacy of H(1)-type antihistamines can be assessed by using MoDCs. METHODS: We examined the suppressive effects of 1 H(2)-type antihistamine (cimetidine) and 5 different H(1)-type antihistamines (cetirizine, diphenhydramine, ketotifen, olopatadine, and emedastine) on the induction of CD86 and IL-8 production by MoDCs from 23 healthy individuals stimulated with histamine. We also examined the responses of MoDCs from 13 patients with chronic urticaria to these antihistamines, and compared the in vitro efficacy with the actual clinical response to antihistamines evaluated by patient and physician assessments. RESULTS: All the antihistamines we examined suppressed the increase of CD86(+) cells after histamine stimulation in a dose-dependent fashion, and all H(1)-type antihistamines were more efficacious than cimetidine. IL-8 production stimulated with histamine was also suppressed by cetirizine, ketotifen, and olopatadine. Unexpectedly, the suppressive effect of these antihistamines on the CD86 augmentation was highly variable among different healthy control participants. Interestingly, in 10 of 13 cases of chronic urticaria, this in vitro analysis of antihistamines correlated with the clinical response to antihistamines. CONCLUSION: This study suggests that the evaluation of antihistamines using MoDCs can be a useful method for the screening of effective antihistamines, for the comparison of the efficacy of antihistamines, and for predicting the efficacy of antihistamines on an individual basis.

p38 Mitogen-activated protein kinase and extracellular signal-regulated kinases play distinct roles in the activation of dendritic cells by two representative haptens, NiCl2 and 2,4-dinitrochlorobenzene.

Previous studies have demonstrated that haptens induce several phenotypic and functional changes of dendritic cells in vivo as well as in vitro. Although recently, the crucial role of p38 mitogen-activated protein kinase has been reported in the activation of dendritic cells by haptens, the signal transduction elements involved in each phenotypic and functional changes that occur in the activation of dendritic cells by haptens remain unknown. Therefore, we examined the role of mitogen-activated protein kinases and nuclear factor-kappaB in the signal transduction of dendritic cells stimulated with two representative haptens, i.e., NiCl2 and 2,4-dinitrochlorobenzene. Human monocyte-derived dendritic cells stimulated with 2,4-dinitrochlorobenzene induced the phosphorylation of p38 and stress-activated protein kinase/c-jun N-terminal kinases, whereas NiCl2 induced that of p44/42 extracellular signal-regulated kinases, p38, and stress-activated protein kinase/c-jun N-terminal kinases. In addition, NiCl2 phosphorylated inhibitor kappaB and activated nuclear factor-kappaB. In contrast, primary irritants, e.g., benzalkonium chloride, or sodium lauryl sulfate, did not activate these signal transduction pathways. By using specific inhibitors for extracellular signal-regulated kinases and p38 pathways, PD98059 and SB203580, respectively, we demonstrated that the augmentation of CD86, HLA-DR, and CD83, and the production of interleukin-8 along with its increased mRNA expression by monocyte-derived dendritic cells stimulated with 2,4-dinitrochlorobenzene, and the augmentation of CD83 and the interleukin-12 p40 production by monocyte-derived dendritic cells stimulated with NiCl2, were suppressed by SB203580, whereas PD98059 suppressed the production of interleukin-1beta and tumor necrosis factor-alpha, together with their increased mRNA expression by monocyte-derived dendritic cells treated with NiCl2. On the other hand, in spite of the activation of nuclear factor-kappaB by monocyte-derived dendritic cells stimulated with NiCl2, nuclear factor-kappaB inhibitor did not significantly affect the phenotypic and functional changes in the activation of monocyte-derived dendritic cells. These data indicate that NiCl2 and 2,4-dinitrochlorobenzene stimulate different signal transduction pathways in monocyte-derived dendritic cells, and subsequently induce different phenotypic and functional changes in them.

Macrophage colony-stimulating factor in cooperation with transforming growth factor-beta1 induces the differentiation of CD34+ hematopoietic progenitor cells into Langerhans cells under serum-free conditions without granulocyte-macrophage colony-stimulating factor.

Macrophage colony-stimulating factor has not been considered as a factor responsible for dendritic cell or Langerhans cell development from hematopoietic progenitor cells. In this study, we examined whether macrophage colony-stimulating factor could be used instead of granulocyte-macrophage colony-stimulating factor for the in vitro development of Langerhans cells from hematopoietic progenitor cells. We replaced granulocyte-macrophage colony-stimulating factor with macrophage colony-stimulating factor from a serum-free culture containing granulocyte-macrophage colony-stimulating factor, stem cell factor, Flt3 ligand, tumor necrosis factor-alpha, and transforming growth factor-beta1. This serum-free culture medium containing macrophage colony-stimulating factor, but not granulocyte-macrophage colony-stimulating factor (macrophage colony-stimulating factor culture), could induce CD1a+ Birbeck granule+ Langerin+ E-cadherin+ factor-like XIIIa Langerhans cells. As a control, the culture of hematopoietic progenitor cells in this culture medium depleted of macrophage colony-stimulating factor or transforming growth factor-beta1 resulted in far fewer or null CD1a+ cells, respectively. Macrophage colony-stimulating factor increased the number of CD1a+ cells in a concentration-dependent fashion. These macrophage colony-stimulating factor-induced Langerhans cells were different from granulocyte-macrophage colony-stimulating factor-induced Langerhans cells in their decreased expression of CD11c and their immature phenotype. The decreased expression of CD11c, however, was recovered by culturing them with granulocyte-macrophage colony-stimulating factor, while they acquired a mature phenotype qby granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, interleukin-1alpha, or lipo-polysaccharide. Macrophage colony-stimulating factor-induced Langerhans cells could stimulate allogeneic T cells. Interestingly, we could keep the growth and immature phenotypes of macrophage colony-stimulating factor-induced Langerhans cells for at least 28 d of culture. These studies demonstrated that macrophage colony-stimulating factor in cooperation with transforming growth factor-beta1 could induce Langerhans cell development from hematopoietic progenitor cells in vitro without granulocyte-macrophage colony-stimulating factor, which suggests the possibility that macrophage colony-stimulating factor plays a part in the Langerhans cell development in vivo. In addition, the culture using macrophage colony-stimulating factor presents a novel culture system to enable a large-scale and long-term culture of immature Langerhans cells.

H1 and H2 histamine receptors are absent on Langerhans cells and present on dermal dendritic cells.

Human monocyte-derived dendritic cells (MoDC) have both histamine H1 and H2 receptors and can induce CD86 expression by histamine. Nevertheless, it has not been reported whether human epidermal Langerhans cells (LC) have histamine receptors or not. In this study, using RT-PCR, we investigated the expression of H1 and H2 receptor mRNA on DC with the features of LC (LC-like DC) that were generated in vitro from peripheral blood monocytes, LC derived from CD34+ hematopoietic progenitor cells, and LC obtained from human epidermis. We compared the histamine-induced CD86 expression among these cells. In contrast to MoDC, LC and LC-like DC did not express H1 or H2 receptors. In addition, they could not augment the CD86 expression by histamine. Interestingly, when transforming growth factor-beta1 (TGF-beta1) was added to the culture of MoDC, the expression of H1 and H2 receptors and the histamine-induced CD86 expression were abrogated in a concentration-dependent fashion. Finally, in the assessment of the cell surface expression of histamine receptors using fluorescence-labeled histamine, histamine could bind to MoDC and dermal dendritic cells obtained from the skin, whereas there was no specific binding of histamine to LC-like DC or LC obtained from the skin. These data suggest that LC do not express either H1 or H2 receptors, mainly because of the effect of TGF-beta1. This made a striking contrast with the expression of the functional H1 and H2 receptors on MoDC and dermal dendritic cells.