Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation.
Dendritic cells (DCs) involved in proinflammatory immune responses derive mainly from peripheral monocytes, and the cells subsequently mature and migrate into the inflammatory micromilieu. Here we report that suppressing of 15-lipoxygenase-1 led to a substantial reduction in DC spreading and podosome formation in vitro. The surface expression of CD83 was significantly lower in both sh-15-lipoxygenase-1 (15-LOX-1)-transduced cells and DCs cultivated in the presence of a novel specific 15-LOX-1 inhibitor. The T-cell response against tetanus-pulsed DCs was only affected to a minor extent on inhibition of 15-LOX-1. In contrast, endocytosis and migration ability of DCs were significantly suppressed on 15-LOX-1 inhibition. The expression of 15-LOX-1 in DCs was also demonstrated in affected human skin in atopic and contact dermatitis, showing that the enzyme is indeed expressed in inflammatory diseases in vivo. This study demonstrated that inhibiting 15-LOX-1 led to an impaired podosome formation in DCs, and consequently suppressed antigen uptake and migration capacity. These results indicated that 15-LOX-1 is a potential target for inhibiting the trafficking of DCs to lymphoid organs and inflamed tissues and decreasing the inflammatory response attenuating symptoms of certain immunologic and inflammatory disorders such as dermatitis.-Han, H., Liang, X., Ekberg, M., Kritikou, J. S., Brunnström, Å., Pelcman, B., Matl, M., Miao, X., Andersson, M., Yuan, X., Schain, F., Parvin, S., Melin, E., Sjöberg, J., Xu, D., Westerberg, L. S., Björkholm, M., Claesson, H.-E. Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation.
Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; ya.han@ki.se.|Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Hongya
H
Han
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Xiuming
X
Liang
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Monica
M
Ekberg
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Joanna S
JS
Kritikou
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Åsa
Å
Brunnström
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden.
Benjamin
B
Pelcman
Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Maria
M
Matl
Clinical Pharmacology Group, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; and.
Xinyan
X
Miao
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Margareta
M
Andersson
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Xiaotian
X
Yuan
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Frida
F
Schain
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Selina
S
Parvin
Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
Eva
E
Melin
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Jan
J
Sjöberg
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Dawei
D
Xu
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Lisa S
LS
Westerberg
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Magnus
M
Björkholm
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Hans-Erik
HE
Claesson
D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007801:Langerhans Cells / Q000378:metabolism; D009000:Monocytes; D000069261:Podosomes / Q000502:physiology*; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000235:genetics / Q000378:metabolism
C498970:CD84 protein, human; D016207:Cytokines; D000071176:Signaling Lymphocytic Activation Molecule Family; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase
arachidonic acid; cell migration; dermatitis; endocytosis