A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock

The regulation of monocyte function and the inhibition of TNF-cu 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 surv ived (1/15, 6.7% died). Susceptible mer(kd) mice exhibited edema, leukocyte infiltration, and signs of endotoxic shock that correlated with higher lev els of TNF-alpha found in the serum of merkd mice as compared with wild-typ e control animals. Death due to LPS-induced endotoxic shock in mer(kd) mice was blocked by administration of anti-TNF-alpha Ab, suggesting that overpr oduction of this cytokine was principally responsible fur the heightened su septibility, The increase in TNF-alpha production appeared to be the result of a substantial increase in the LPS-dependent activation of NF-kappa B nu clear translocation resulting in greater TNF-alpha production by macrophage s from mer(kd) mice. Thus, Mer receptor tyrosine kinase signaling participa tes in a novel inhibitory pathway in macrophages important for regulating T NF-alpha secretion and attenuating endotoxic shock.