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1.
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
2.
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
3.
J Allergy Clin Immunol ; 117(2): 411-7, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16461142

ABSTRACT

BACKGROUND: IL-31 is a novel T-cell-derived cytokine that induces severe pruritus and dermatitis in transgenic mice, and signals through a heterodimeric receptor composed of IL-31 receptor A and oncostatin M receptor. OBJECTIVE: To investigate the role of human IL-31 in pruritic and nonpruritic inflammatory skin diseases. METHODS: The expression of IL-31 was analyzed by quantitative real-time PCR in skin samples of healthy individuals and patients with chronic inflammatory skin diseases. Moreover, IL-31 expression was analyzed in nonlesional skin of atopic dermatitis patients after allergen or superantigen exposure, as well as in stimulated leukocytes. The tissue distribution of the IL-31 receptor heterodimer was investigated by DNA microarray analysis. RESULTS: IL-31 was significantly overexpressed in pruritic atopic compared with nonpruritic psoriatic skin inflammation. Highest IL-31 levels were detected in prurigo nodularis, one of the most pruritic forms of chronic skin inflammation. In vivo, staphylococcal superantigen rapidly induced IL-31 expression in atopic individuals. In vitro, staphylococcal enterotoxin B but not viruses or T(H)1 and T(H)2 cytokines induced IL-31 in leukocytes. In patients with atopic dermatitis, activated leukocytes expressed significantly higher IL-31 levels compared with control subjects. IL-31 receptor A showed most abundant expression in dorsal root ganglia representing the site where the cell bodies of cutaneous sensory neurons reside. CONCLUSION: Our findings provide a new link among staphylococcal colonization, subsequent T-cell recruitment/activation, and pruritus induction in patients with atopic dermatitis. Taken together, these findings show that IL-31 may represent a novel target for antipruritic drug development.


Subject(s)
Dermatitis, Atopic/immunology , Interleukins/metabolism , Pruritus/immunology , T-Lymphocytes/immunology , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/physiopathology , Ganglia, Spinal/metabolism , Humans , Lymphocyte Activation , Prurigo/immunology , Prurigo/metabolism , Pruritus/metabolism , Pruritus/physiopathology , Psoriasis/immunology , Psoriasis/metabolism , Receptors, Interleukin/metabolism , Staphylococcus aureus/immunology , Superantigens/immunology , Up-Regulation
4.
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
5.
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
6.
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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