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)) profoundl y alters cytokine release in response to subsequent LPS(a) activation. These qualitative and quantitative alterations in cytokine release ha ve been termed macrophage reprogramming. Macrophage activation by LPS is thought to occur via a mechanism involving an early protein tyrosin e kinase (PTK) phosphorylation step, PTK inhibition with genistein or herbimycin A blocks LPS(a)-stimulated secretion of tumor necrosis fact or (TNF) and interleukin-1 (IL-1). In this study we investigated wheth er a PTK pathway participates in LPS(p) pretreatment reprogramming, We show that LPS(p) pretreatment inhibited TNF and augmented IL-1 releas e in response to subsequent LPS(p) stimulation, Blockade of PTK activa tion pathways during the interval when macrophages were exposed to LPS (p) prevented mitogen-activated protein kinase phosphorylation, as wel l as LPS(p)-stimulated release of TNF and IL-1, but did not block LPS( p) reprogramming effects, We conclude that LPS(p) pretreatment reprogr amming of macrophage cytokine production does not require PTK activati on.