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Published online before print September 7, 2006

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(Journal of Leukocyte Biology. 2006;80:1522-1528.)
© 2006 by Society for Leukocyte Biology

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^*,,,1

^* 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

¹ Correspondence: Cancer Research Institute, Botterell Hall, Room A309, Queens University, Kingston, Ontario K7L 3N6, Canada. E-mail: greerp{at}post.queensu.ca

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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