Potential role of the chemokine receptors CXCR3, CCR4, and the integrin alphaEbeta7 in the pathogenesis of psoriasis vulgaris.
Various adhesion molecules have been implicated in T lymphocyte binding to dermal vascular endothelium in psoriasis vulgaris, but the chemotactic signals that promote subsequent homing into the adjacent dermis and overlying epidermis are poorly defined. We studied chemokine receptor (CCR1-CCR5, CXCR1-CXCR3), chemokine (interferon-gamma inducible protein 10 [IP-10]), monokine induced by interferon-gamma (MIG), thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), and adhesion molecule (cutaneous lymphocyte antigen [CLA], E-selectin, lymphocyte function-associated antigen-1 [LFA-1], intercellular adhesion molecule-1 [ICAM-1], very late antigen 4 [VLA-4], vascular cell adhesion molecule-1 [VCAM-1], alphaEbeta7, and E-cadherin) expression in psoriasis by immunohistology, flow cytometry, and molecular techniques. CXCR3 and CCR4 were expressed by dermal CD3+ lymphocytes, and their chemokine ligands, IP-10, MIG, TARC, and MDC, were up-regulated in psoriatic lesions. Keratinocytes stimulated with tumor necrosis factor-alpha and interferon-gamma up-regulated expression of IP-10, MIG, and MDC mRNA, whereas dermal endothelial cells, similarly stimulated, up-regulated expression of IP-10, MDC, and TARC mRNA, suggesting that these cell types were sources of the chemokines detected in biopsies. There was enhanced expression of E-selectin, CLA, LFA-1, ICAM-1, VLA-4, VCAM-1, and alphaEbeta7 in psoriatic lesions versus nonlesional skin. Finally, intra-epidermal CLA+ and alphaEbeta7+ T lymphocytes selectively expressed the chemokine receptor CXCR3. Collectively, these data suggest that CXCR3 and CCR4 may be involved in T lymphocyte trafficking to the psoriatic dermis and that CXCR3 is selectively involved in subsequent T cell homing to the overlying epidermis.
Rottman
J B
JB
Millennium Pharmaceuticals, Cambridge, Massachusetts 02139, USA. jrottman@mpi.com
Smith
T L
TL
Ganley
K G
KG
Kikuchi
T
T
Krueger
J G
JG
D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D001706:Biopsy; D002478:Cells, Cultured; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019742:Chemokines, CC / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019040:E-Selectin / Q000276:immunology / Q000378:metabolism; D004727:Endothelium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D011565:Psoriasis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000032:analysis / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515354:CCR4 protein, human; C063419:CTAGE1 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019742:Chemokines, CC; D019743:Chemokines, CXC; D019040:E-Selectin; D039041:Integrin alpha4beta1; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; C070709:integrin alphaEbeta7; D018799:Intercellular Adhesion Molecule-1