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

Journal of Leukocyte Biology

Sean A. Parsons¹  Peter A. Greer² 

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

关键词: knockout mouse;    lipopolysaccharide;    cytokine;    endocytosis;    tyrosine kinase;   

DOI  :  10.1189/jlb.0506350

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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-α 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-α production. Cultured Fps/Fes null macrophages also displayed prolonged LPS-induced degradation of IκB-α, increased phosphorylation of the p65 subunit of NF-κB, 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.

【 授权许可】

Unknown