ABSTRACT
BACKGROUND: Overexpression of vascular endothelial growth factor (VEGF) in epidermal lesions of psoriasis is well documented; however, its underlying mechanisms are largely unknown. We have recently demonstrated that vasoactive intestinal peptide (VIP) induces the production of cytokines such as interleukin-6 and stem cell factor from keratinocytes, thereby contributing to the development of inflammatory dermatoses such as psoriasis. OBJECTIVES: In this study, we attempted to determine whether VIP could increase the production of VEGF in human keratinocytes. METHODS: We examined the expression of VEGF using reverse transcription-polymerase chain reaction, immunocytochemistry, enzyme-linked immunosorbent assay and immunoblotting in normal human epidermal keratinocytes and human epidermal keratinocyte cell line DJM-1 cultured in the absence or presence of VIP and/or inflammatory cytokines. RESULTS: We demonstrate that human keratinocytes produced VEGF in a steady state at both mRNA and protein levels. VIP significantly upregulated the production of VEGF in keratinocytes in a dose- and time-dependent manner. The VIP-mediated production of VEGF was further enhanced by inflammatory cytokines such as interferon-gamma, tumour necrosis factor-alpha and interleukin-4, with maximum enhancement being observed with the combination of VIP and interferon-gamma. CONCLUSIONS: VIP and other cytokines from nerve endings, mast cells and local inflammatory cells are capable of enhancing VEGF production from epidermal keratinocytes, which may underlie excessive angiogenesis and vasodilation in skin lesions of psoriasis.
Subject(s)
Cytokines/metabolism , Keratinocytes/metabolism , Psoriasis/metabolism , Vascular Endothelial Growth Factor A/biosynthesis , Vasoactive Intestinal Peptide/metabolism , Blotting, Western , Cell Line , Enzyme-Linked Immunosorbent Assay , Epidermal Cells , Humans , Immunohistochemistry , Reverse Transcriptase Polymerase Chain ReactionSubject(s)
Dermatomycoses/diagnosis , Exophiala , Abscess/microbiology , Aged , Humans , Immunocompromised Host , MaleSubject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/complications , Pemphigoid, Bullous/complications , Pemphigus/complications , Aged , Autoantigens/immunology , Biopsy , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Male , Non-Fibrillar Collagens/immunology , Pemphigoid, Bullous/diagnosis , Pemphigoid, Bullous/immunology , Pemphigus/diagnosis , Pemphigus/immunology , Skin/pathology , Collagen Type XVIISubject(s)
Immunoglobulin G/immunology , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Cutaneous/diagnosis , Pemphigoid, Bullous/diagnosis , Tacrolimus/therapeutic use , Adult , Enzyme-Linked Immunosorbent Assay , Fluorescent Antibody Technique, Indirect , Humans , Male , Pemphigoid, Bullous/drug therapy , Pemphigoid, Bullous/immunologySubject(s)
Erythema/diagnosis , Urticaria/diagnosis , Vasculitis/diagnosis , Aged , Erythema/drug therapy , Erythema/pathology , Female , Histamine Antagonists/administration & dosage , Histamine Antagonists/therapeutic use , Humans , Purpura , Reserpine/administration & dosage , Reserpine/therapeutic use , Urticaria/drug therapy , Urticaria/pathology , Vasculitis/drug therapy , Vasculitis/pathologySubject(s)
Herpes Simplex/complications , Kaposi Varicelliform Eruption/complications , Pemphigus/complications , Aged, 80 and over , Azathioprine/therapeutic use , Diagnosis, Differential , Drug Therapy, Combination , Fatal Outcome , Herpes Simplex/drug therapy , Humans , Immunosuppressive Agents/therapeutic use , Kaposi Varicelliform Eruption/drug therapy , Male , Pemphigus/drug therapy , Prednisolone/therapeutic useSubject(s)
Autoantibodies/blood , Autoantigens/immunology , Minocycline/therapeutic use , Non-Fibrillar Collagens/immunology , Pemphigoid, Bullous/drug therapy , Prednisolone/therapeutic use , Drug Therapy, Combination , Humans , Immunoglobulin G/blood , Leg Dermatoses/drug therapy , Male , Middle Aged , Collagen Type XVIISubject(s)
Lymphoma/immunology , Molluscum Contagiosum/immunology , Molluscum Contagiosum/metabolism , Ubiquitin/metabolism , Adult , Antineoplastic Combined Chemotherapy Protocols , Cyclophosphamide , Doxorubicin , Fatal Outcome , Female , Humans , Immunocompromised Host , Lymphoma/diagnosis , Lymphoma/drug therapy , Molluscum Contagiosum/diagnosis , Prednisolone , VincristineSubject(s)
Blister/etiology , Blister/pathology , Coma/complications , Dermatitis, Contact/pathology , Rhabdomyolysis/complications , Aged , Alcohol Drinking/adverse effects , Blister/diagnosis , Coma/etiology , Dermatitis, Contact/diagnosis , Diagnosis, Differential , Humans , Male , Skin/pathologyABSTRACT
BACKGROUND: Th2 and Th1 cells have been suggested to express CCR3/CCR4 and CCR5/CXCR3, respectively. OBJECTIVE: We examined CCR3, CCR4, CCR5 and CXCR3 expression and cytokine production in peripheral blood CD4+ T cells from patients with atopic dermatitis (AD), which has been postulated to be a Th2-type cell-mediated disease, and then analysed the possible correlation between these values and the levels of several clinical parameters. METHODS: Intracellular cytokine production and chemokine receptor expression in peripheral blood CD4+ T cells from 40 AD patients and 20 sex- and age-matched healthy control subjects were studied by flow cytometry. RESULTS: The frequencies of IL-4- and IL-13-producing CD4+ T cells from patients with AD were significantly higher than those from healthy control subjects (IL-4:3.9 +/- 2.1% vs. 1.6 +/- 0.7%, P = 0.0005, IL-13:4.0 +/- 2.1% vs. 1.8 +/- 0.8%, P = 0.0023), whereas the frequencies of IL-2- and IFN-gamma-producing CD4+ T cells were significantly decreased in AD patients (IL-2:38.1 +/- 10.3% vs. 51.3 +/- 6.3%, P = 0.0003, IFN-gamma: 9.9 +/- 3.5% vs. 26.4 +/- 4.6%, P < 0.0001). The percentage of CCR4+ cells in CD4+ CD45RO+ T cells in AD patients was significantly higher than that in healthy control subjects (24.4 +/- 8.0% vs. 10.9 +/- 2.3%, P < 0.0001) and was correlated positively with the total serum IgE, serum lactic dehydrogenase (LDH) level, eosinophil number, eruption score, and IL-4 and IL-13 secretion in CD4+ T cells, and inversely with IL-2 and IFN-gamma secretion in CD4+ T cells. In contrast, CCR3 was not detected on circulating CD4+ T cells even in AD patients. On the other hand, the percentage of CCR5+ or CXCR3+ cells in CD4+ CD45RO+ T cells in AD patients was significantly decreased (CCR5:23.2 +/- 7.0% vs. 28.4 +/- 5.4%, P = 0.023, CXCR3:29.9 +/- 11.4% vs. 38.5 +/- 6.7%, P = 0.028) and was positively correlated with eruption score (P < 0.05). Multiple regression analyses showed that the percentage of CCR4 expression highly correlated with serum IgE, LDH, eosinophil number and eruption in AD patients. CONCLUSION: CCR4+ cells might be involved in the aetiopathogenesis of AD.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cytokines/metabolism , Dermatitis, Atopic/immunology , Receptors, Chemokine/analysis , Adolescent , Adult , Case-Control Studies , Child , Eosinophils/immunology , Flow Cytometry , Humans , Immunoglobulin E/blood , Interferon-gamma/metabolism , Interleukin-13/metabolism , Interleukin-2/metabolism , Interleukin-4/metabolism , L-Lactate Dehydrogenase/blood , Leukocyte Count , Logistic Models , Receptors, CCR4 , Th1 Cells/immunology , Th2 Cells/immunologySubject(s)
BCG Vaccine/adverse effects , Granuloma Annulare/etiology , Child , Granuloma Annulare/pathology , Humans , MaleABSTRACT
Vasoactive intestinal peptide has been suggested to play some roles in inflammatory dermatoses such as atopic dermatitis and psoriasis. The aim of this study is to clarify the precise mechanisms of how vasoactive intestinal peptide is implicated in the pathogenesis of these disorders. We investigated the expression of vasoactive intestinal peptide and its receptors in normal human fibroblasts and keratinocytes, as well as in a human epidermal keratinocyte cell line DJM-1, using reverse transcription polymerase chain reaction and northern blotting. Type I VIP receptor mRNA was expressed in normal human keratinocytes and DJM-1 cells, and the latter also expressed type II receptor in lesser amounts. Neither type I nor type II VIP receptor mRNA was detected in fibroblasts, and vasoactive intestinal peptide transcript was not found in any cells examined. Type I VIP receptor mRNA was upregulated by Th1 cytokines (interferon-gamma), Th2 cytokines (interleukin-4), and tumor necrosis factor alpha, as well as vasoactive intestinal peptide itself, suggesting the presence of an autoregulatory loop. Vasoactive intestinal peptide increased cAMP production and cell proliferation of DJM-1 cells, and also induced the production of inflammatory cytokines such as interleukin-6, interleukin-8, and RANTES. The production of cAMP and cytokines was abrogated by a type I VIP receptor selective antagonist, indicating that type I receptor mediates these effects. Overall, these results suggest that upregulation of vasoactive intestinal peptide receptors by cytokines from inflammatory cells in the dermis enhances the proliferation and cytokine production of keratinocytes in response to vasoactive intestinal peptide from nerve endings. This cytokine network around keratinocytes may be involved in the pathogenesis of inflammatory dermatoses.
Subject(s)
Fibroblasts/metabolism , Keratinocytes/metabolism , Receptors, Vasoactive Intestinal Peptide/physiology , Vasoactive Intestinal Peptide/physiology , Cell Division/drug effects , Cell Line , Cyclic AMP/biosynthesis , Cytokines/biosynthesis , Cytokines/pharmacology , DNA/biosynthesis , Humans , RNA, Messenger/metabolism , Receptors, Vasoactive Intestinal Peptide/antagonists & inhibitors , Receptors, Vasoactive Intestinal Peptide/classification , Receptors, Vasoactive Intestinal Peptide/genetics , Receptors, Vasoactive Intestinal Peptide/metabolism , Receptors, Vasoactive Intestinal Polypeptide, Type I , Reference Values , Vasoactive Intestinal Peptide/pharmacologyABSTRACT
A 47-year-old man with an angiosarcoma of the right lower extremity was cured with mainly surgery and radiotherapy despite an inguinal metastasis. Histologically, the amputation stump of the metastatic tumour showed invasion by tumour. Radiotherapy, chemotherapy, and treatment with interleukin-2 was added. Ten years later he has had no recurrence.
Subject(s)
Hemangiosarcoma/secondary , Hemangiosarcoma/therapy , Leg , Humans , Lymphatic Metastasis , Male , Middle AgedABSTRACT
We studied the effects of stem cell factor (SCF) on human skin mast cell (HSMC) survival and the proliferation of neurofibroma (NF) cells in transplanted NF in nude mice. Small pieces of cutaneous NF from a patient with von Recklinghausen's disease were transplanted subcutaneously into nude mice. Recombinant human SCF (10 or 100 ng) was injected six or seven times around the NF transplantation sites over 11 days (i.e. every other day). The number of HSMCs was reduced in vehicle-injected NF compared to the amount present before transplantation. In contrast, NF-transplanted animals that were injected with SCF (10 or 100 ng) showed preservation of mast cell numbers in the tissue. Using computerized image analysis, mast cell size in SCF-treated NF transplants was significantly altered (larger at the 10 ng dose, and smaller at the 100 ng dose) compared with the size before transplantation or in vehicle-injected tissue. Furthermore, at the higher SCF dose (100 ng) PCNA-positive NF cells showed a significant increase. These results indicate that HSMCs in transplanted NF tissue retain their capacity to respond to SCF in vivo, and that SCF contributes to the regulation of both HSMC survival and size in cutaneous NF. In addition, activated HSMCs induced by SCF may be involved in the growth of cutaneous NF in von Recklinghausen's disease. Thus, this experimental model may be useful in the study of the cellular interactions between HSMCs and other stromal cells in cutaneous NF.