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FASEB J. 2017 Feb;31(2):491-504. doi: 10.1096/fj.201600679RR. Epub 2016 Oct 17.

Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation.

Author information

1
Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; ya.han@ki.se.
2
Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
3
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
4
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden.
5
Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
6
Clinical Pharmacology Group, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; and.
7
Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.

Abstract

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.

KEYWORDS:

arachidonic acid; cell migration; dermatitis; endocytosis

PMID:
27825104
DOI:
10.1096/fj.201600679RR
[Indexed for MEDLINE]

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