LPS pretreatment reprograms macrophage LPS‐stimulated TNF and IL‐1 release without protein tyrosine kinase activation

Pretreatment of macrophages with low‐dose endotoxin (LPS p ) profoundly alters cytokine release in response to subsequent LPS a activation. These qualitative and quantitative alterations in cytokine release have been termed macrophage reprogramming. Macrophage activation by LPS is thought to occur via a mechanism involving an early protein tyrosine kinase (PTK) phosphorylation step. PTK inhibition with genistein or herbimycin A blocks LPS a ‐stimulated secretion of tumor necrosis factor (TNF) and interleukin‐1 (IL‐1). In this study we investigated whether a PTK pathway participates in LPS p pretreatment reprogramming. We show that LPSp pretreatment inhibited TNF and augmented IL‐1 release in response to subsequent LPS a stimulation. Blockade of PTK activation pathways during the interval when macrophages were exposed to LPSp prevented mitogen‐activated protein kinase phosphorylation, as well as LPS p ‐stimulated release of TNF and IL‐1, but did not block LPS p reprogramming effects. We conclude that LPS p pretreatment reprogramming of macrophage cytokine production does not require PTK activation. J. Leukoc. Biol . 61: 88–95; 1997.