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The Fps/Fes kinase regulates the inflammatory response to endotoxin through down‐regulation of TLR4, NF‐κB activation, and TNF‐α secretion in macrophages
Author(s) -
Parsons Sean A.,
Greer Peter A.
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0506350
Subject(s) - secretion , tlr4 , tumor necrosis factor alpha , biology , nf κb , kinase , inflammatory response , inflammation , microbiology and biotechnology , nfkb1 , iκb kinase , macrophage , signal transduction , immunology , biochemistry , gene , transcription factor , in vitro
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.