Up-regulation of macrophage inflammatory protein-3 alpha/CCL20 and CC chemokine receptor 6 in psoriasis.
Autoimmunity plays a key role in the immunopathogenesis of psoriasis; however, little is known about the recruitment of pathogenic cells to skin lesions. We report here that the CC chemokine, macrophage inflammatory protein-3 alpha, recently renamed CCL20, and its receptor CCR6 are markedly up-regulated in psoriasis. CCL20-expressing keratinocytes colocalize with skin-infiltrating T cells in lesional psoriatic skin. PBMCs derived from psoriatic patients show significantly increased CCR6 mRNA levels. Moreover, skin-homing CLA+ memory T cells express high levels of surface CCR6. Furthermore, the expression of CCR6 mRNA is 100- to 1000-fold higher on sorted CLA+ memory T cells than other chemokine receptors, including CXCR1, CXCR2, CXCR3, CCR2, CCR3, and CCR5. In vitro, CCL20 attracted skin-homing CLA+ T cells of both normal and psoriatic donors; however, psoriatic lymphocytes responded to lower concentrations of chemokine and showed higher chemotactic responses. Using ELISA as well as real-time quantitative PCR, we show that cultured primary keratinocytes, dermal fibroblasts, and dermal microvascular endothelial and dendritic cells are major sources of CCL20, and that the expression of this chemokine can be induced by proinflammatory mediators such as TNF-alpha/IL-1 beta, CD40 ligand, IFN-gamma, or IL-17. Taken together, these findings strongly suggest that CCL20/CCR6 may play a role in the recruitment of T cells to lesional psoriatic skin.
Homey
B
B
DNAX Research Institute, Palo Alto, CA 94304, USA.
Dieu-Nosjean
M C
MC
Wiesenborn
A
A
Massacrier
C
C
Pin
J J
JJ
Oldham
E
E
Catron
D
D
Buchanan
M E
ME
Müller
A
A
deWaal Malefyt
R
R
Deng
G
G
Orozco
R
R
Ruzicka
T
T
Lehmann
P
P
Lebecque
S
S
Caux
C
C
Zlotnik
A
A
D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D023201:CD40 Ligand; D054418:Chemokine CCL20; D019742:Chemokines, CC; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; C108355:CCL20 protein, human; C106311:CCR6 protein, human; C063419:CTAGE1 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D007375:Interleukin-1; D020381:Interleukin-17; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007371:Interferon-gamma