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1.
Eur J Med Res ; 23(1): 4, 2018 Jan 16.
Article in English | MEDLINE | ID: mdl-29338773

ABSTRACT

BACKGROUND: Wound healing represents a dynamic process involving directional migration of different cell types. Chemokines, a family of chemoattractive proteins, have been suggested to be key players in cell-to-cell communication and essential for directed migration of structural cells. Today, the role of the chemokine network in cutaneous wound healing is not fully understood. Unraveling the chemokine-driven communication pathways in this complex process could possibly lead to new therapeutic strategies in wound healing disorders. METHODS: We performed a systematic, comprehensive time-course analysis of the expression and function of a broad variety of cytokines, growth factors, adhesion molecules, matrixmetalloproteinases and chemokines in a murine cutaneous wound healing model. RESULTS: Strikingly, chemokines were found to be among the most highly regulated genes and their expression was found to coincide with the expression of their matching receptors. Accordingly, we could show that resting and activated human primary keratinocytes (CCR3, CCR4, CCR6, CXCR1, CXCR3), dermal fibroblasts (CCR3, CCR4, CCR10) and dermal microvascular endothelial cells (CCR3, CCR4, CCR6, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3) express a distinct and functionally active repertoire of chemokine receptors. Furthermore, chemokine ligand-receptor interactions markedly improved the wound repair of structural skin cells in vitro. CONCLUSION: Taken together, we here present the most comprehensive analysis of mediators critically involved in acute cutaneous wound healing. Our findings suggest therapeutic approaches for the management of wound closure by targeting the chemokine network.


Subject(s)
Fibroblasts/metabolism , Keratinocytes/metabolism , Receptors, Chemokine/metabolism , Wound Healing , Animals , Cells, Cultured , Chemokines/genetics , Chemokines/metabolism , Female , Fibroblasts/physiology , Humans , Keratinocytes/physiology , Matrix Metalloproteinases/genetics , Matrix Metalloproteinases/metabolism , Mice , Mice, Inbred BALB C , Receptors, Chemokine/genetics
2.
Neoplasia ; 11(7): 651-61, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19568410

ABSTRACT

Recent studies have demonstrated that the chemokine receptor CXCR4 plays a crucial role in organ-specific metastasis formation. Although a variety of studies showed the expression of chemokine receptors, in particular, CXCR4, by gastrointestinal tumors, the precise mechanisms of chemokine receptor-mediated homing of cancer cells to specific sites of metastasis remained elusive. Here, we used liver metastatic human HEP-G2 hepatoma and HT-29LMM colon cancer cells expressing functional CXCR4 to dissect the metastatic cascade by intravital fluorescence microscopy. Immunohistochemistry revealed that the CXCR4 ligand CXCL12 is expressed by endothelial cells and likely Kupffer cells lining the liver sinusoids. Tumor cell adhesion and extravasation in vivo was quantitatively analyzed using intravital fluorescence microscopy. Treatment of cells with an anti-CXCR4 antibody did not affect cell adhesion but significantly impaired tumor cell extravasation (HEP-G2; isotype control: 22.3% +/- 4.3% vs anti-CXCR4: 6.0% +/- 5.0%, P < .001). In addition, pretreatment of tumor cells with the ligand CXCL12 enhanced the activation of the small GTPases Rho, Rac, and cdc42 as well as tumor cell extravasation without affecting tumor cell adhesion within liver sinusoids. Taken together, the findings of the present study provide first in vivo insights into the early events of chemokine ligand/receptor-mediated liver metastasis formation of tumor cells and define tumor cell extravasation rather than tumor cell arrest as the rate-limiting event.


Subject(s)
Chemokine CXCL12/metabolism , Neoplasm Invasiveness/pathology , Neoplasm Metastasis/pathology , Receptors, CXCR4/metabolism , Cell Adhesion/physiology , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Flow Cytometry , Humans , Immunohistochemistry , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Microscopy, Fluorescence , Reverse Transcriptase Polymerase Chain Reaction
3.
Proc Natl Acad Sci U S A ; 104(48): 19055-60, 2007 Nov 27.
Article in English | MEDLINE | ID: mdl-18025475

ABSTRACT

The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.


Subject(s)
Carcinoma, Basal Cell/immunology , Carcinoma, Squamous Cell/immunology , Chemokine CCL27/physiology , Gene Expression Regulation, Neoplastic , Neoplasm Proteins/physiology , Skin Neoplasms/immunology , Tumor Escape/physiology , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Carcinoma, Basal Cell/genetics , Carcinoma, Squamous Cell/genetics , Chemokine CCL27/antagonists & inhibitors , Chemokine CCL27/biosynthesis , Chemokine CCL27/genetics , Cytotoxicity, Immunologic , Down-Regulation , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/physiology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Keratinocytes/metabolism , Melanoma, Experimental/genetics , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Mice , Mice, Inbred C57BL , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Photosensitivity Disorders/immunology , Photosensitivity Disorders/metabolism , Precancerous Conditions/immunology , Precancerous Conditions/metabolism , Proto-Oncogene Proteins p21(ras)/physiology , Signal Transduction , Skin Neoplasms/genetics
4.
J Allergy Clin Immunol ; 119(6): 1470-80, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17337293

ABSTRACT

BACKGROUND: As clinical and histological features of allergic and irritant contact dermatitis share common characteristics, the differentiation between them in the preclinical and clinical evaluations of chemicals remains difficult. OBJECTIVE: To identify the differences in the underlying immunological mechanisms of chemical-induced allergic or irritant skin responses. METHODS: We systematically studied the involvement of chemokines in both diseases by quantitative real-time polymerase chain reaction in mice and humans. The cellular origin of relevant chemokines and receptors was determined using immunohistochemistry; functional relevance was demonstrated in vitro by transwell chemotaxis and in vivo by adoptive transfer experiments using a model of hapten-induced murine contact hypersensitivity. RESULTS: Independent of overall skin inflammation, chemical-induced allergic and irritant skin responses showed distinct molecular expression profiles. In particular, chemokine genes predominantly regulated by T-cell effector cytokines demonstrated differential upregulation in hapten-specific skin inflammation. Notably, the expression of CXCR3 ligands, such as CXCL9 (Mig) and CXCL10 (IP-10), was upregulated in chemical-induced allergic skin responses when compared with irritant skin responses. Furthermore, we showed that inflammatory chemokines such as CXCL10 prime leukocytes to respond to CXCL12 (SDF-1), increasing their recruitment both in vitro and in vivo. CONCLUSION: We provide important insights into the molecular basis of chemical-induced allergic and irritant contact dermatitis, identify novel markers suitable for their differentiation, and demonstrate the cooperation of inflammatory and homeostatic chemokines in the recruitment of pathogenic leukocyte subsets. CLINICAL IMPLICATIONS: Molecular differences between both diseases represent the basis for new approaches to diagnostics and therapy.


Subject(s)
Chemokines/biosynthesis , Chemokines/genetics , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/immunology , Dermatitis, Irritant/diagnosis , Dermatitis, Irritant/immunology , Immunologic Memory , T-Lymphocyte Subsets/immunology , Animals , Biomarkers/metabolism , Cell Movement/immunology , Cells, Cultured , Chemokines/physiology , Dermatitis, Allergic Contact/pathology , Dermatitis, Irritant/metabolism , Disease Models, Animal , Female , Humans , Mice , Mice, Inbred BALB C , T-Lymphocyte Subsets/metabolism
5.
Int J Cancer ; 118(9): 2147-57, 2006 May 01.
Article in English | MEDLINE | ID: mdl-16331601

ABSTRACT

Head and neck carcinomas are histologically and clinically heterogeneous. While squamous cell carcinomas (SCC) are characterized by lymphogenous spread, adenoid cystic carcinomas (ACC) disseminate preferentially hematogenously. To study cellular and molecular mechanisms of organ-specific metastasis, we used SCC and ACC cell lines and tumor tissues, obtained from patients with primary or metastatic disease. Comprehensive analysis at the mRNA and protein level of human chemokine receptors showed that SCC and ACC cells exhibited distinct and nonrandom expression profiles for these receptors. SCC predominantly expressed receptors for chemokines homeostatically expressed in lymph nodes, including CC chemokine receptor (CCR) 7 and CXC chemokine receptor (CXCR)5. No difference in expression of chemokine receptors was seen in primary SCC and corresponding lymph node metastases. In contrast to SCC, ACC cells primarily expressed CXCR4. In chemotaxis assays, ACC cells were responsive to CXCL12, the ligand for CXCR4. Exposure of ACC cells to cisplatin resulted in upregulation of CXCR4 on the cell surface, which was repressed by the transcriptional inhibitor, alpha-amanitin. Treatment of ACC cells with CXCL12 resulted in the activation of Akt and ERK1/2 pathways. Furthermore, CXCL12 suppressed the rate of apoptosis induced by cisplatin in ACC cells, suggesting that signaling via CXCR4 may be part of a tumor cell survival program. Discrimination of the chemokine receptor profile in SCC and ACC in vitro and in tissues provided insights into their distinct biologic and clinical characteristics as well as indications that chemokine receptors might serve as future therapeutic targets in these malignancies.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Adenoid Cystic/secondary , Carcinoma, Squamous Cell/secondary , Cisplatin/pharmacology , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/pathology , Receptors, Chemokine/analysis , Apoptosis , Cell Survival , Gene Expression Profiling , Humans , Neoplasm Metastasis , RNA, Messenger/analysis , Receptors, Chemokine/biosynthesis , Signal Transduction
6.
Arthritis Rheum ; 52(5): 1504-16, 2005 May.
Article in English | MEDLINE | ID: mdl-15880822

ABSTRACT

OBJECTIVE: To investigate the activation and recruitment pathways of relevant leukocyte subsets during the initiation and amplification of cutaneous lupus erythematosus (LE). METHODS: Quantitative real-time polymerase chain reaction was used to perform a comprehensive analysis of all known chemokines and their receptors in cutaneous LE lesions, and the cellular origin of these chemokines and receptors was determined using immunohistochemistry. Furthermore, cytokine- and ultraviolet (UV) light-mediated activation pathways of relevant chemokines were investigated in vitro and in vivo. RESULTS: In the present study, we identified the CXCR3 ligands CXCL9 (interferon-gamma [IFNgamma]-induced monokine), CXCL10 (IFNgamma-inducible protein 10), and CXCL11 (IFN-inducible T cell alpha chemoattractant) as being the most abundantly expressed chemokine family members in cutaneous LE. Expression of these ligands corresponded with the presence of a marked inflammatory infiltrate consisting of mainly CXCR3-expressing cells, including skin-homing lymphocytes and blood dendritic cell antigen 2-positive plasmacytoid dendritic cells (PDCs). Within cutaneous LE lesions, PDCs accumulated within the dermis and were activated to produce type I IFN, as detected by the expression of the IFNalpha-inducible genes IRF7 and MxA. IFNalpha, in turn, was a potent and rapid inducer of CXCR3 ligands in cellular constituents of the skin. Furthermore, we demonstrated that the inflammatory CXCR3 ligands cooperate with the homeostatic chemokine CXCL12 (stromal cell-derived factor 1) during the recruitment of pathogenically relevant leukocyte subsets. Moreover, we showed that UVB irradiation induces the release of CCL27 (cutaneous T cell-attracting chemokine) from epidermal compartments into dermal compartments and up-regulates the expression of a distinct set of chemokines in keratinocytes. CONCLUSION: Taken together, our data suggest an amplification cycle in which UV light-induced injury induces apoptosis, necrosis, and chemokine production. These mechanisms, in turn, mediate the recruitment and activation of autoimmune T cells and IFNalpha-producing PDCs, which subsequently release more effector cytokines, thus amplifying chemokine production and leukocyte recruitment, finally leading to the development of a cutaneous LE phenotype.


Subject(s)
Chemokines, CXC/immunology , Intercellular Signaling Peptides and Proteins/immunology , Leukocytes/immunology , Lupus Erythematosus, Cutaneous/immunology , Radiation Injuries/immunology , Ultraviolet Rays/adverse effects , Cells, Cultured , Chemokine CXCL10 , Chemokine CXCL11 , Chemokine CXCL9 , Humans , Lupus Erythematosus, Cutaneous/pathology , Lymphocyte Activation
7.
J Immunol ; 174(8): 5082-91, 2005 Apr 15.
Article in English | MEDLINE | ID: mdl-15814739

ABSTRACT

Atopic dermatitis represents a chronically relapsing skin disease with a steadily increasing prevalence of 10-20% in children. Skin-infiltrating T cells, dendritic cells (DC), and mast cells are thought to play a crucial role in its pathogenesis. We report that the expression of the CC chemokine CCL1 (I-309) is significantly and selectively up-regulated in atopic dermatitis in comparison to psoriasis, cutaneous lupus erythematosus, or normal skin. CCL1 serum levels of atopic dermatitis patients are significantly higher than levels in healthy individuals. DC, mast cells, and dermal endothelial cells are abundant sources of CCL1 during atopic skin inflammation and allergen challenge, and Staphylococcus aureus-derived products induce its production. In vitro, binding and cross-linking of IgE on mast cells resulted in a significant up-regulation of this inflammatory chemokine. Its specific receptor, CCR8, is expressed on a small subset of circulating T cells and is abundantly expressed on interstitial DC, Langerhans cells generated in vitro, and their monocytic precursors. Although DC maintain their CCR8+ status during maturation, brief activation of circulating T cells recruits CCR8 from intracytoplamic stores to the cell surface. Moreover, the inflammatory and atopy-associated chemokine CCL1 synergizes with the homeostatic chemokine CXCL12 (SDF-1alpha) resulting in the recruitment of T cell and Langerhans cell-like DC. Taken together, these findings suggest that the axis CCL1-CCR8 links adaptive and innate immune functions that play a role in the initiation and amplification of atopic skin inflammation.


Subject(s)
Chemokines, CC/metabolism , Dermatitis, Atopic/immunology , Langerhans Cells/immunology , Receptors, Chemokine/metabolism , T-Lymphocytes/immunology , Allergens/administration & dosage , Animals , Antigens, Bacterial , Case-Control Studies , Cell Differentiation , Cell Movement , Cells, Cultured , Chemokine CCL1 , Chemokine CCL17 , Chemokine CXCL12 , Chemokines, CC/blood , Chemokines, CXC/metabolism , Child , Cytokines/metabolism , Dermatitis, Atopic/etiology , Dermatitis, Atopic/pathology , Humans , Immunoglobulin E/metabolism , In Vitro Techniques , Inflammation Mediators/metabolism , Langerhans Cells/pathology , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/pathology , Mast Cells/immunology , Mice , Monocytes/immunology , Monocytes/pathology , Psoriasis/immunology , Psoriasis/pathology , Receptors, CCR8 , Staphylococcus aureus/immunology , T-Lymphocytes/pathology
8.
J Immunol ; 173(9): 5810-7, 2004 Nov 01.
Article in English | MEDLINE | ID: mdl-15494534

ABSTRACT

Atopic dermatitis is a chronic inflammatory skin disease with a steadily increasing prevalence. Exposure to allergens or bacterial superantigens triggers T and dendritic cell (DC) recruitment and induces atopic skin inflammation. In this study, we report that among all known chemokines CCL18/DC-CK1/PARC represents the most highly expressed ligand in atopic dermatitis. Moreover, CCL18 expression is associated with an atopic dermatitis phenotype when compared with other chronic inflammatory skin diseases. DCs either dispersed within the dermis or clustering at sites showing perivascular infiltrates are abundant sources of CCL18. In vitro, microbial products including LPS, peptidoglycan, and mannan, as well as the T cell-derived activation signal CD40L, induced CCL18 in monocytes. In contrast to monocytes, monocyte-derived, interstitial-type, and Langerhans-type DCs showed a constitutive and abundant expression of CCL18. In comparison to Langerhans cells, interstitial-type DCs produced higher constitutive levels of CCL18. In vivo, topical exposure to the relevant allergen or the superantigen staphylococcal enterotoxin B, resulted in a significant induction of CCL18 in atopic dermatitis patients. Furthermore, in nonatopic NiSO4-sensitized individuals, only relevant allergen but not irritant exposure resulted in the induction of CCL18. Taken together, findings of the present study demonstrate that CCL18 is associated with an atopy/allergy skin phenotype, and is expressed at the interface between the environment and the host by cells constantly screening foreign Ags. Its regulation by allergen exposure and microbial products suggests an important role for CCL18 in the initiation and amplification of atopic skin inflammation.


Subject(s)
Allergens/immunology , Antigens, Bacterial/immunology , Chemokines, CC/physiology , Dendritic Cells/immunology , Dendritic Cells/microbiology , Dermatitis, Atopic/immunology , Dermatitis, Atopic/microbiology , Staphylococcus/immunology , Cells, Cultured , Chemokines, CC/biosynthesis , Chemokines, CC/metabolism , Chronic Disease , Dendritic Cells/pathology , Dermatitis, Atopic/pathology , Endothelium, Vascular/cytology , Endothelium, Vascular/immunology , Endothelium, Vascular/metabolism , Enterotoxins/immunology , Fibroblasts/immunology , Fibroblasts/metabolism , Humans , Keratinocytes/immunology , Keratinocytes/metabolism , Langerhans Cells/immunology , Langerhans Cells/metabolism , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/microbiology , Lupus Erythematosus, Systemic/pathology , Phenotype , Psoriasis/immunology , Psoriasis/microbiology , Psoriasis/pathology , Skin/blood supply , Skin/immunology , Skin/metabolism , Superantigens/immunology
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