Published online before print September 7, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0506350

Received for publication May 24, 2006.
Revised June 30, 2006.
Accepted for publication July 25, 2006.

Article

The Fps/Fes kinase regulates the inflammatory response to endotoxin through down-regulation of TLR4, NF-B activation, and TNF- secretion in macrophages

Sean A. Parsons ^* and Peter A. Greer ^*@

*Division of Cancer Biology and Genetics, Department of Biochemistry, and Department of Pathology and Molecular Medicine, Queen’s University Cancer Research Institute, Kingston, Ontario, Canada

^@ To whom correspondence should be addressed. E-mail: greerp{at}post.queensu.ca.

Abstract

Fps/Fes and Fer are members of a distinct subfamily of cytoplasmic protein tyrosine kinases that have recently been implicated in the regulation of innate immunity. Previous studies showed that mice lacking Fps/Fes are hypersensitive to systemic LPS challenge, and Fer-deficient mice displayed enhanced recruitment of leukocytes in response to local LPS challenge. This study identifies physiological, cellular, and molecular defects that contribute to the hyperinflammatory phenotype in Fps/Fes null mice. Plasma TNF- levels were elevated in LPS challenged Fps/Fes null mice as compared with wild-type mice and cultured Fps/Fes null peritoneal macrophages treated with LPS showed increased TNF- production. Cultured Fps/Fes null macrophages also displayed prolonged LPS-induced degradation of IB-, increased phosphorylation of the p65 subunit of NF-B, and defective TLR4 internalization, compared with wild-type macrophages. Together, these observations provide a likely mechanistic basis for elevated proinflammatory cytokine secretion by Fps/Fes null macrophages and the increased sensitivity of Fps/Fes null mice to endotoxin. We posit that Fps/Fes modulates the innate immune response of macrophages to LPS, in part, by regulating internalization and down-regulation of the TLR4 receptor complex.

Key Words: knockout mouse • lipopolysaccharide • cytokine • endocytosis • tyrosine kinase

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