[Show abstract][Hide abstract] ABSTRACT: Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family, has been implicated in the pathogenesis of connective tissue diseases characterized by extracellular matrix remodeling. Since serum MMP-13 levels reflect disease severity of systemic sclerosis and localized scleroderma, we evaluated the clinical significance of serum MMP-13 levels in eosinophilic fasciitis (EF). All the EF patients had serum MMP-13 levels lower than the mean – 2SD of healthy controls. Serum MMP-13 levels were also significantly decreased in EF patients compared with diffuse cutaneous systemic sclerosis, limited cutaneous systemic sclerosis, and generalized morphea patients. Although serum MMP-13 levels did not reflect any clinical and serological features of EF, these results indicate that MMP-13 may be involved in the development of this disease.
The Journal of Dermatology 07/2014; 41(8). DOI:10.1111/1346-8138.12563 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Autotaxin (ATX), secreted mainly from adipose tissue, functions as a lysophospholipase D (lysoPLD) to hydrolyze lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). ATX-LPA signaling is implicated in a wide range of physiological and pathophysiological processes including immune response.
The present study measured serum ATX antigen levels in patients with various autoimmune diseases using a recently developed automated enzyme immunoassay. In addition, serum lysoPLD activity was assessed by measuring choline liberation from the substrate LPC. Moreover, the effect of prednisolone (PSL) on mRNA expression of ATX was evaluated using cultured adipose tissue from mice.
Decreased serum ATX antigen levels were observed after the initiation of treatment with PSL. The decreased levels recovered during tapering of PSL dose in a dose-dependent manner without exacerbation of disease activity. Moreover, decreased ATX mRNA expression in PSL-treated cultured murine adipose tissue suggested that the effect of PSL on serum ATX may have resulted from changes in adipose tissue ATX expression.
Our results suggest that measurement of serum ATX antigen level may be clinically useful for the assessment of steroid treatment effect and drug compliance with steroids. Furthermore, our findings provide many novel insights into the biosynthesis, physiological functions, pathological roles, and clinical significance of circulating ATX.
Clinica chimica acta; international journal of clinical chemistry 10/2012; 415. DOI:10.1016/j.cca.2012.10.003 · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary cutaneous anaplastic large cell lymphoma (PCALCL) is defined as anaplastic large cell lymphoma localized to the skin without extracutaneous involvement at the time of diagnosis. Histologically, PCALCL is characterized by a dense nodular infiltrate of large lymphocytes, extending into the deep dermis or subcutis. Epidermotropism is sometimes, but not frequently, seen. We herein report a case of PCALCL with prominent epidermotropism. A 63-year-old Japanese woman was referred to our hospital with a red nodule and indurated erythema in 1997. Histological findings of a skin biopsy specimen from a red nodule were typical of PCALCL, however, biopsy specimens from indurated erythema showed remarkable epidermotropism. Tumor cells were positive for CD4, and CD30, but negative for CD3 and CD8. She was diagnosed with PCALCL. In 2007, skin biopsy was performed again, which showed large atypical lymphocytes in the upper dermis with mild epidermotropism. Tumor cells expressed in both CC chemokine receptor 4 and CXC chemokine receptor 3, which may explain prominent epidermotropism in this case.
International journal of hematology 03/2012; 95(6):711-5. DOI:10.1007/s12185-012-1062-5 · 1.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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-1β 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.
The Journal of Immunology 11/2011; 188(1):436-44. DOI:10.4049/jimmunol.1003746 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The lymph transports tissue-resident dendritic cells (DCs) to regional lymph nodes (LNs), having important roles in immune function. The biological effects on tissue inflammation following lymphatic flow obstruction in vivo, however, are not fully known. In this study, we investigated the role of the lymphatic system in contact hypersensitivity (CHS) responses using k-cyclin transgenic (kCYC(+/-)) mice, which demonstrate severe lymphatic dysfunction. kCYC(+/-) mice showed enhanced ear swelling to both DNFB and FITC, as well as stronger irritant responses to croton oil compared with wild-type littermates. Consistently, challenged ears of kCYC(+/-) mice exhibited massive infiltrates of inflammatory cells. In contrast, DC migration to regional LNs, drainage of cell-free antigen to LNs, antigen-specific IFN-γ production, and lymphocyte proliferation were impaired during the sensitization phase of CHS in kCYC(+/-) mice. Transfer experiments using lymphocytes from sensitized mice and real-time PCR analysis of cytokine expression using challenged ear revealed that ear swelling was enhanced because of impaired lymphatic flow. Collectively, we conclude that insufficient lymphatic drainage augments apparent inflammation to topically applied allergens and irritants. The findings add insight into the clinical problem of allergic and irritant contact dermatitis that commonly occurs in humans with peripheral edema of the lower legs.
[Show abstract][Hide abstract] ABSTRACT: Sarcoidosis is a chronic multisystem disease of unknown origin, which is characterized by T-helper-1 (Th1)-mediated immune responses. On the other hand, atopic dermatitis (AD) is characterized by Th2-mediated immune responses. We recently experienced an interesting case of AD in which the patient experienced a significant resolution of AD after the onset of sarcoidosis. We herein describe the details of his clinical course and discuss the impact of negative cross-regulation between Th1 and Th2 immune responses.
Modern Rheumatology 08/2011; 21(4):406-9. DOI:10.1007/s10165-010-0404-5 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: β-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). β-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 β-glucan-stimulated NHEKs. No response to LPS from Escherichia coli was seen. Dectin-1 is known as the major receptor for β-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 β-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 β-glucan-induced IL-8 production by NHEKs. Thus, high calcium, ATP, and poly(I:C) augment the cytokine and chemokine production by β-glucan-stimulated NHEKs. Dectin-1 is present on NHEKs and may have an important role in cell response to β-glucan.
[Show abstract][Hide abstract] ABSTRACT: Semaphorin 7A (Sema7A) expressed on activated T cells stimulates cytokine production in monocytes through its receptor, α1β1 integrin.
To study the significance of Sema7A expressed on keratinocytes in skin inflammation where interaction between keratinocytes and β1-integrin expressing inflammatory cells, such as monocytes, takes place.
The regulation of Sema7A expression on keratinocytes by various cytokines was studied by flow cytometry and immunoblot. β1-integrin expressing human monocyte cell line, THP-1 cells, were co-cultured with paraformaldehyde-fixed normal human epidermal keratinocytes (NHK) and IL-8 production by THP-1 cells was studied. The significance of β1-integrin or Sema7A within this cell interaction was examined by the experiments using β1-integrin blocking antibody or Sema7A siRNA.
IFN-γ and TNF-α slightly increased Sema7A expression, while IL-4 decreased it. Among cytokines tested, TGF-β1 most strikingly increased the Sema7A expression on NHK. When NHK was stimulated by TGF-β1, paraformaldehyde-fixed, and co-cultured with THP-1 cells, IL-8 production by THP-1 cells was increased compared to THP-1 cells only. When THP-1 cells were pretreated with β1-integrin blocking antibody, this increase in IL-8 production by THP-1 cells was inhibited. Likewise, when NHK were pretreated with Sema7A siRNA before fixation and co-cultured with THP-1 cells, increase in IL-8 production by THP-1 cells was inhibited.
Our results suggest that Sema7A on keratinocytes and β1-integrin on monocytes contribute to monocyte activation by keratinocytes within skin inflammation, such as psoriasis or wound.
[Show abstract][Hide abstract] ABSTRACT: CCL21 expression by lymphatic endothelial cells (LECs) is essential for migration of CCR7+ immune cells from skin to regional lymph nodes (LNs). We investigated the importance of mitogen-activated protein kinase (MAPK) signaling in CCL21 expression by ECs in vitro and in vivo. Normal human dermal lymphatic microvascular ECs (HMVEC-dLy) stimulated in vitro with oncostatin M (OSM) expressed high amounts of CCL21 mRNA. CCL21 protein expression by HMVEC-dLy was also markedly increased by OSM compared with unstimulated cultures. Marked phosphorylation of MAPK 44/42 was detected in HMVEC-dLy stimulated by OSM. CCL21 expression by HMVEC-dLy was blocked by a JAK inhibitor 1, JAK3 inhibitor, and U0126 (a MAPK kinase inhibitor) in vitro, all of which blocked phosphorylation of MAPK 44/42. In addition, injection of U0126 into murine skin significantly decreased CCL21 mRNA and protein expression. Moreover, injection of U0126 before sensitization decreased migration of dendritic cells to draining LNs and decreased contact hypersensitivity responses. In summary, these results suggest that the MAPK pathway is important for CCL21 expression by LECs in vitro and in vivo. Blocking MAPK signaling within skin may offer a novel approach to treatment of inflammatory skin diseases.
[Show abstract][Hide abstract] ABSTRACT: Some chemokines are known to accelerate wound healing. However, there has been no report on the relationship between Thymus and activation-regulated chemokine (TARC)/CC chemokine ligand (CCL) 17 and wound healing. The purpose of this study was to determine whether CCL17 enhances response to cutaneous injury.
We made a full-thickness dorsal wound in transgenic (Tg) mice, in which CCL17 was overexpressed and in control mice. Wound size was compared over the course of time. We evaluated the effect of CCL17 on fibroblast migration by a Boyden chamber assay and a scratch wound assay.
Wound closure in Tg mice was more accelerated than in control mice. CCL17 enhanced nerve growth factor (NGF) production by 2B4, which is mouse T cell hybridoma. Further, in the wound area of Tg mice, the number of CCR4(+) fibroblasts, CCR4(+) lymphocytes and mast cells was increased compared to control mice, as was the number of NGF(+) lymphocytes around the wound area. In vitro assay, CCL17 was shown to enhance the migration of fibroblasts.
These results suggest that CCL17 accelerates wound healing, mainly by enhancing fibroblast migration, and possibly by increasing NGF(+) lymphocytes and mast cells, which have independently been reported to enhance wound healing.
[Show abstract][Hide abstract] ABSTRACT: CCR3 is a specific marker of anaplastic large cell lymphoma (ALCL) cells. ALCL cells also express CCL11, a ligand for CCR3, leading to the hypothesis that CCL11 may play an autocrine role in ALCL progression. In this study, we investigated a role of CCL11 in cell survival and growth of human Ki-JK cells, established from an ALCL patient, and murine EL-4 lymphoma cells. Both Ki-JK and EL-4 cells expressed cell surface CCR3. CCL11 increased cell survival rates of Ki-JK cells in a dose-dependent manner, whereas it promoted EL-4 cell proliferation. Furthermore, CCL11 induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in both Ki-JK cells and EL-4 cells. Cell survival and tumor proliferation promoted by CCL11 was completely blocked by inhibition of ERK phosphorylation. CCL11 induced expression of antiapoptotic proteins, Bcl-xL and survivin, in Ki-JK cells. CCL11 also enhanced tumor growth of EL-4 and Ki-JK cells in vivo. Consistent with these results, tumor cells of cutaneous ALCL expressed CCR3 and increased levels of phosphorylated ERK1/2, Bcl-xL, and survivin in situ. Thus, our findings prompt a novel therapeutic approach to treat relapses of an aggressive form of lymphoma based on the discovery that a cell surface marker of disease functions as a critical autocrine growth receptor.
Cancer Research 03/2011; 71(6):2056-65. DOI:10.1158/0008-5472.CAN-10-3764 · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and countermeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is a inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level.
Allergology International 03/2011; 60(2):205-20. DOI:10.2332/allergolint.11-RAI-0333 · 2.46 Impact Factor