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By
From the Department of Laboratory Medicine, University of California, San Francisco, California
94143-0724
Lipopolysaccharide (LPS) stimulates immune responses by interacting with the membrane
receptor CD14 to induce the generation of cytokines such as tumor necrosis factor (TNF)-
,
interleukin (IL)-1, and IL-6. The mechanism by which the LPS signal is transduced from the
extracellular environment to the nuclear compartment is not well defined. Recently, an increasing amount of evidence suggests that protein tyrosine kinases especially the Src-family kinases Hck, Fgr, and Lyn, play important roles in LPS signaling. To directly address the physiological function of Hck, Fgr and Lyn in LPS signaling, a genetic approach has been used to
generate null mutations of all three kinases in a single mouse strain. hck
/
fgr
/
lyn
/
mice are
moderately healthy and fertile; macrophages cultured from these mice express normal levels of
CD14 and no other Src-family kinases were detected. Although the total protein phosphotyrosine level is greatly reduced in macrophages derived from hck
/
fgr
/
lyn
/
mice, functional
analyses indicate that both elicited peritoneal (PEMs) and bone marrow-derived macrophages
(BMDMs) from triple mutant mice have no major defects in LPS-induced activation. Nitrite production and cytokine secretion (IL-1, IL-6, and TNF-
) are normal or even enhanced in
hck
/
fgr
/
lyn
/
macrophages after LPS stimulation. The development of tumor cell cytotoxicity is normal in triple mutant BMDMs and only partially impaired in PEMs after LPS stimulation. Furthermore, the activation of the ERK1/2 and JNK kinases, as well as the transcription
factor NF-
B, are the same in normal and mutant macrophages after LPS stimulation. The current study provides direct evidence that three Src-family kinases Hck, Fgr, and Lyn are not
obligatory for LPS-initiated signal transduction.
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