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Role of integrin-linked kinase in leukocyte recruitment
Erik B Friedrich1, Sumita Sinha, Ling Li
1Center for Immunology and Inflammatory Diseases, Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Insights
Integrin-linked kinase (ILK) is activated by chemokines and regulates leukocyte adhesion. This study shows ILK controls integrin avidity, impacting how leukocytes attach to endothelial cells.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Chemokines coordinate leukocyte adhesion and migration via integrin avidity modulation.
- The precise signaling pathways governing these processes are not fully understood.
Purpose of the Study:
- To investigate the role of integrin-linked kinase (ILK) in chemokine-mediated leukocyte adhesion.
- To elucidate the signaling pathway involving ILK activation by chemokines.
Main Methods:
- Biochemical inhibitor studies were used to determine ILK activation pathways.
- Functional assays under flow conditions assessed the impact of ILK on leukocyte adhesion.
- Overexpression of wild-type ILK in human monocytic cells was performed.
Main Results:
- Integrin-linked kinase (ILK) is highly expressed in human mononuclear cells and activated by monocyte chemoattractant protein-1.
- Chemokine-triggered ILK activation occurs downstream of phosphoinositide 3-kinase.
- Overexpression of ILK reduced beta(1) integrin/vascular cell adhesion molecule-1-dependent firm adhesion.
Conclusions:
- Integrin-linked kinase (ILK) plays a critical role in regulating leukocyte integrin avidity.
- ILK is implicated in the dynamic signaling events controlling leukocyte adhesion to endothelial cells.
Abstract:
Chemokines modulate leukocyte integrin avidity to coordinate adhesion and subsequent transendothelial migration, although the sequential signaling pathways involved remain poorly characterized. Here we show that integrin-linked kinase (ILK), a 59-kDa serine-threonine protein kinase that interacts principally with beta(1) integrins, is highly expressed in human mononuclear cells and is activated by exposure of leukocytes to the chemokine monocyte chemoattractant protein-1. Biochemical inhibitor studies show that chemokine-triggered activation of ILK is downstream of phosphoinositide 3-kinase. In functional assays under physiologically relevant flow conditions, overexpression of wild-type ILK in human monocytic cells diminishes beta(1) integrin/vascular cell adhesion molecule-1-dependent firm adhesion to human endothelial cells. These data implicate ILK in the dynamic signaling events involved in the regulation of leukocyte integrin avidity for endothelial substrates.