ABSTRACT
Psoriasis is a T-helper (Th)1/Th17-mediated, chronic inflammatory dermatitis that is commonly treated with topical corticosteroids and vitamin D3 analogs. The combination of a topical corticosteroid and vitamin D3 analog showed superior efficacy to each alone in clinical trials; however, the mechanisms by which the topical corticosteroid and vitamin D3 analog exert their effects on lesional skin in combination and each alone remain unknown. In this study, we examined the effects of combined calcipotriol (Cal)/betamethasone dipropionate (BD) ointment on psoriasis in vivo, utilizing imiquimod (IMQ)-induced murine psoriasiform skin inflammation, compared with each alone. Vehicle, Cal/BD, Cal or BD was applied on the shaved back skin for 3 consecutive days. Then, IMQ was applied for 6 consecutive days. Twenty-four hours after the last IMQ treatment, the murine skin was evaluated clinically and pathologically. mRNA expressions were examined by quantitative polymerase chain reaction. All ointments alleviated IMQ-induced psoriasiform skin inflammation clinically in comparison with vehicle application. Cal/BD suppressed mRNA expressions of cytokines involved in psoriasis pathogenesis such as interleukin (IL)-17A and IL-22 efficiently. Cal alone induced IL-10 expression, whereas BD alone reduced IL-6 mRNA expression and the number of phosphorylated signal transducer and activator of transcription 3-positive cells in lesional skin. Our study revealed that Cal and BD have different effects on IMQ-induced psoriasiform skin. Some of the immune effects of Cal and BD may be additive or synergistic, which may account for the superior clinical efficacy of their combination.
Subject(s)
Betamethasone/analogs & derivatives , Calcitriol/analogs & derivatives , Dermatologic Agents/pharmacology , Glucocorticoids/physiology , Psoriasis/drug therapy , Administration, Cutaneous , Animals , Betamethasone/pharmacology , Betamethasone/therapeutic use , Calcitriol/pharmacology , Calcitriol/therapeutic use , Cytokines/metabolism , Dermatologic Agents/therapeutic use , Disease Models, Animal , Drug Synergism , Drug Therapy, Combination/methods , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Glucocorticoids/therapeutic use , Humans , Imiquimod/toxicity , Mice , Ointments , Psoriasis/blood , Psoriasis/immunology , Psoriasis/pathology , Skin/drug effects , Skin/immunology , Skin/pathology , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/drug effects , Th17 Cells/immunology , Th17 Cells/metabolismABSTRACT
BACKGROUND: Psoriasis is a Th1/Th17-mediated inflammatory dermatosis treated with topical corticosteroids and vitamin D3 analogs (VD3 As). OBJECTIVE: To compare the effects of a VD3 A maxacalcitol and betamethasone valerate (BV) steroid lotion on topical imiquimod (IMQ)-induced psoriasiform skin inflammation. METHODS: Female BALB/c mice were treated with vehicle, maxacalcitol or BV lotion on the skin for 3 days, and IMQ cream for 6 days. q-PCR, H&E, immunohistochemistry and immunofluorescence studies were performed on skin samples. Additionally, mice were treated with vehicle, maxacalcitol or BV lotion for 3 days and CD4+CD25+ regulatory T cells (Tregs) and CD4+CD25- cells from each group were isolated from lymph nodes. Adoptive transfer of the cells was performed on recipient mice which were treated with IMQ cream for 6 days, and skin samples were obtained for q-PCR and H&E staining. RESULTS: Maxacalcitol and BV were comparable in regards clinical improvement, although maxacalcitol reduced the MHC Class II+ inflammatory cell infiltration more than BV in IMQ skin. While both treatments downregulated IL-17 A, IL-17 F, IL-22, IL-12p40, TNF-α and IL-6 mRNA expression levels, only maxacalcitol downregulated IL-23p19 expression. Significantly increased Foxp3+ cell infiltrations and IL-10 expression were noted in maxacalcitol-treated IMQ skin. Adoptive transfer of Treg cells from maxacalcitol-treated donor mice improved IMQ-induced inflammation clinically and histopathologically more than the recipients of Treg cells from BV-treated donor groups, showing reduced levels of inflammatory cytokines and increased IL-10 expression. CONCLUSION: These results indicate that maxacalcitol reduces psoriasiform skin inflammation by inducing Treg cells as well as downregulating IL-23 and IL-17 production.
Subject(s)
Calcitriol/analogs & derivatives , Dermatologic Agents/pharmacology , Interleukin-17/metabolism , Interleukin-23/metabolism , Psoriasis/drug therapy , T-Lymphocytes, Regulatory/drug effects , Adoptive Transfer , Animals , Betamethasone Valerate/pharmacology , Betamethasone Valerate/therapeutic use , Calcitriol/pharmacology , Calcitriol/therapeutic use , Dermatologic Agents/therapeutic use , Down-Regulation , Female , Humans , Imiquimod/immunology , Interleukin-17/immunology , Interleukin-23/immunology , Mice , Mice, Inbred BALB C , Psoriasis/immunology , Psoriasis/pathology , Skin/cytology , Skin/immunology , Skin/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Treatment OutcomeABSTRACT
Systemic plasmacytosis is a rare skin disorder characterized by marked infiltration of plasma cells in the dermis. IgG4-related disease is pathologically characterized by lymphoplasmacytic infiltration rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, accompanied by elevated levels of serum IgG4. Reports of cases of systemic plasmacytosis with abundant infiltration of IgG4+ plasma cells has led to discussion about the relationship between systemic plasmacytosis and IgG4-related disease. This study examined IgG4+/IgG+ plasma cell ratios in 4 patients with systemic plasmacytosis and 12 patients with other skin diseases that show marked infiltration of plasma cells. Furthermore, we examined whether these cases met one of the pathological diagnostic criteria for IgG4-related disease (i.e. IgG4+/IgG plasma cells ratio of over 40%). Only one out of 4 patients with systemic plasmacytosis met the criterion. These results suggest that systemic plasmacytosis and IgG4-related disease are distinct diseases.
Subject(s)
Autoimmune Diseases/immunology , Immunoglobulin G/analysis , Plasma Cells/immunology , Skin Diseases/immunology , Skin/immunology , Adult , Aged , Autoimmune Diseases/blood , Autoimmune Diseases/diagnosis , Biomarkers/analysis , Biomarkers/blood , Biopsy , Female , Humans , Immunoglobulin G/blood , Immunohistochemistry , Male , Middle Aged , Plasma Cells/pathology , Predictive Value of Tests , Skin/pathology , Skin Diseases/blood , Skin Diseases/diagnosisABSTRACT
Accumulating epidemiologic evidence has revealed that metabolic syndrome is an independent risk factor for psoriasis development and is associated with more severe psoriasis. Adiponectin, primarily recognized as a metabolic mediator of insulin sensitivity, has been newly drawing attention as a mediator of immune responses. Here we demonstrate that adiponectin regulates skin inflammation, especially IL-17-related psoriasiform dermatitis. Mice with adiponectin deficiency show severe psoriasiform skin inflammation with enhanced infiltration of IL-17-producing dermal Vγ4+γδ-T cells. Adiponectin directly acts on murine dermal γδ-T cells to suppress IL-17 synthesis via AdipoR1. We furthermore demonstrate here that the adiponectin level of skin tissue as well as subcutaneous fat is decreased in psoriasis patients. IL-17 production from human CD4- or CD8-positive T cells is also suppressed by adiponectin. Our data provide a regulatory role of adiponectin in skin inflammation, which would imply a mechanism underlying the relationship between psoriasis and metabolic disorders.
Subject(s)
Adiponectin/immunology , Dermatitis/immunology , Interleukin-17/immunology , Psoriasis/immunology , Receptors, Adiponectin/immunology , Skin/immunology , Adiponectin/genetics , Adjuvants, Immunologic/toxicity , Adult , Aminoquinolines/toxicity , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Dermatitis/etiology , Female , Humans , Imiquimod , Immunoblotting , Interleukin-17/metabolism , Interleukin-23/toxicity , Male , Mice , Middle Aged , Real-Time Polymerase Chain Reaction , Receptors, Antigen, T-Cell, gamma-delta/immunology , Reverse Transcriptase Polymerase Chain Reaction , Subcutaneous FatABSTRACT
Contact with fungal pathogens initiates a series of host responses beginning with innate immunity, which leads to fungal recognition and microbial killing. The innate immune system also modulates the adaptive immune responses, leading to the establishment of immunological memory and protection against pathogens. In the case of dimorphic fungi such as Candida albicans and Malassezia, the immune system plays an important role in tolerance and resistance when managing the organisms either as commensal microbiota or invading pathogens, and disruption of this balance can result in pathological consequences for the host. In addition, Malassezia and dermatophytes have immunomodulatory capabilities that allow them to adapt to their environments and they may exert different effects in healthy and diseased skin. Here, we discuss the host immune responses to dermatomycoses caused by dimorphic fungi such as C. albicans and Malassezia as well as dermatophytes such as Trichophyton spp. and Arthroderma benhamiae to gain a better understanding of the mechanisms of the host-dermatomycosis interaction.
Subject(s)
Arthrodermataceae/immunology , Candida albicans/immunology , Cytokines/blood , Dermatomycoses/immunology , Malassezia/immunology , Animals , Humans , Th1 Cells/immunology , Th17 Cells/immunologyABSTRACT
Gout occurs in individuals with hyperuricemia when monosodium urate (MSU) crystals precipitate in tissues and induce acute inflammation via phagocytic cells such as monocytes. MSU crystals have been demonstrated in skin diseases such as tophaceous gout or psoriasis; however, the importance of MSU crystals in the skin is totally unknown. In this study, we found that MSU crystals, through P2Y(6) receptors, stimulated normal human keratinocytes (NHK) to produce IL-1α, IL-8/CXCL8, and IL-6. P2Y(6) receptor expression increased in MSU-stimulated NHK. Both P2Y(6)-specific antagonist and P2Y(6) antisense oligonucleotides significantly inhibited the production of IL-1α, IL-8/CXCL8, and IL-6 by NHK. Similarly, the P2Y(6)-specific antagonist completely inhibited the MSU-induced production of IL-1ß by THP-1 cells, a human monocytic cell line. Remarkably, the P2Y(6)-specific antagonist significantly reduced neutrophil influx in both mouse air pouch and peritonitis models. Thus, these results indicate that the P2Y(6) receptor signaling pathway may be a potential therapeutic target for MSU-associated inflammatory diseases, such as tophaceous gout.
Subject(s)
Antioxidants/adverse effects , Keratinocytes/immunology , Psoriasis/immunology , Purinergic P2 Receptor Antagonists/immunology , Signal Transduction/drug effects , Uric Acid/adverse effects , Animals , Antioxidants/pharmacology , Cell Line , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Gout/immunology , Gout/metabolism , Gout/pathology , Humans , Hyperuricemia/immunology , Hyperuricemia/metabolism , Hyperuricemia/pathology , Inflammation/chemically induced , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Keratinocytes/metabolism , Keratinocytes/pathology , Mice , Mice, Inbred BALB C , Monocytes/immunology , Monocytes/metabolism , Monocytes/pathology , Neutrophil Infiltration/drug effects , Neutrophil Infiltration/immunology , Peritonitis/immunology , Peritonitis/metabolism , Peritonitis/pathology , Psoriasis/chemically induced , Psoriasis/metabolism , Psoriasis/pathology , Purinergic P2 Receptor Antagonists/metabolism , Receptors, Purinergic P2 , Signal Transduction/immunology , Uric Acid/pharmacologyABSTRACT
ß-Glucans are pathogen-associated molecular patterns of fungi such as Candida albicans. Here, we studied their effects on normal human epidermal keratinocytes (NHEKs) from neonatal foreskin, and with high calcium to induce keratinocyte differentiation, danger signals, and pathogen-associated compounds such as adenosine 5'-triphosphate (ATP), poly(I:C), and lipopolysaccharide (LPS). ß-Glucan stimulation significantly increased IL-8, IL-6, and IL-1α production by NHEKs. Well-differentiated NHEKs produced elevated IL-8 levels, whereas ATP, a danger signal, significantly increased IL-8 and IL-6 production, and the pathogen-associated compound, poly(I:C), augmented IL-1α production by ß-glucan-stimulated NHEKs. No response to LPS from Escherichia coli was seen. Dectin-1 is known as the major receptor for ß-glucans on phagocytes and dendritic cells. Dectin-1 mRNA was detected in NHEKs by reverse transcription-PCR. Flow-cytometric analyses confirmed the NHEK cell surface expression of dectin-1. Immunoblotting showed that ß-glucan induced dual phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase (ERK)1/2), and p38 MAPK in NHEKs; these signaling pathways are known to be associated with dectin-1. Treatment with the ERK inhibitor PD98059 and with the p38 kinase inhibitor SB203580 effectively suppressed ß-glucan-induced IL-8 production by NHEKs. Thus, high calcium, ATP, and poly(I:C) augment the cytokine and chemokine production by ß-glucan-stimulated NHEKs. Dectin-1 is present on NHEKs and may have an important role in cell response to ß-glucan.
Subject(s)
Adenosine Triphosphate/pharmacology , Calcium/pharmacology , Immunity, Innate/drug effects , Keratinocytes/drug effects , Keratinocytes/metabolism , Poly I-C/pharmacology , beta-Glucans/pharmacology , Cells, Cultured , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Flavonoids/pharmacology , Humans , Imidazoles/pharmacology , Interleukin-1alpha/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Keratinocytes/cytology , Lectins, C-Type , Membrane Proteins/metabolism , Nerve Tissue Proteins/metabolism , Pyridines/pharmacology , Signal Transduction/drug effects , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Dendritic cells (DCs) are a group of professional antigen-presenting cells, and many genes are known to be associated with their maturation. We compared the transcriptional profiles of immature and mature mouse Langerhans cells using the suppressive, subtractive hybridization method and identified a novel gene of unknown function, termed herein transmembrane protein 123 (Tmem123), of which mRNA expression was enhanced in mature but not in immature Langerhans cells. Its expression was also enhanced in other mature DCs such as bone marrow-derived DCs (BMDCs) and splenic DCs. Interestingly, CD40 expression was up-regulated on mature BMDCs cultured with colchicine concurrently with the enhanced expression of Tmem123 compared with that of fresh BMDCs. Furthermore, the expression of CD40 was enhanced on Tmem123-transfected DC2.4 cells, a mouse BMDC-derived cell line, compared with that on mock-transfected DC2.4 cells. This enhancement of CD40 expression did not occur after deletion of lysosome/endosome targeting YXXÏ motifs (where X is any amino acid and Ï is a bulky hydrophobic amino acid) in the Tmem123 cytoplasmic tail. By stimulation with anti-CD40 monoclonal antibody, these transfectants secreted an increased amount of IL-12/23 p40 compared with mock-transfected DC2.4 cells. Thus, our study demonstrates that Tmem123 may be used as a new maturation marker in DCs and that this molecule may be closely associated with the cell surface expression of CD40.