The regulation of monocyte function and the inhibition of TNF-α production during bacterial sepsis are critical in attenuating adverse host responses to endotoxemia. To study the function of a novel receptor tyrosine kinase, mer, that is expressed in monocytes, we generated mice (mer(kd)) that lack the signaling tyrosine kinase domain. Upon LPS challenge, mer(kd) animals died of endotoxic shock (15/17, 88.2%), whereas control, wild-type mice survived (1/15, 6.7% died). Susceptible mer(kd) mice exhibited edema, leukocyte infiltration, and signs of endotoxic shock that correlated with higher levels of TNF-α found in the serum of mer(kd) mice as compared with wild-type control animals. Death due to LPS-induced endotoxic shock in mer(kd) mice was blocked by administration of anti-TNF-α Ab, suggesting that overproduction of this cytokine was principally responsible for the heightened susceptibility. The increase in TNF-α production appeared to be the result of a substantial increase in the LPS-dependent activation of NF- κB nuclear translocation resulting in greater TNF-α production by macrophages from mer(kd) mice. Thus, Mer receptor tyrosine kinase signaling participates in a novel inhibitory pathway in macrophages important for regulating TNF-α secretion and attenuating endotoxic shock.
|Original language||English (US)|
|Number of pages||6|
|Journal||Journal of Immunology|
|State||Published - Mar 15 1999|
ASJC Scopus subject areas
- Immunology and Allergy