CXCR1 AND CXCR2 ARE RAPIDLY DOWN-MODULATED BY BACTERIAL-ENDOTOXIN THROUGH A UNIQUE AGONIST-INDEPENDENT, TYROSINE KINASE-DEPENDENT MECHANISM

The expression of the seven-transmembrane domain chemokine receptors C XCR1 and CXCR2 modulates neutrophil responsiveness to the chemoattract ant IL-8 and a number of closely related CXC chemokines, In the presen t study, we investigated the mechanism by which bacterial LPS induces the down-modulation of IL-8 responsiveness and CXCR1 and CXCR2 express ion on human neutrophils, Treating neutrophils with LPS reduced IL-8R expression to 55 +/- 5% of the control within 30 min and to 23 +/- 2% within 1 h of stimulation. Furthermore, this down-modulation could not be attributed to increased concentrations of IL-8, TNF-alpha, or IL-1 beta, since ELISA studies indicated that LPS-stimulated neutrophils d id not release detectable amounts of these proteins before 2 h poststi mulation, The tyrosine kinase (TK) inhibitors genistein and herbimycin A attenuated the LPS-mediated down-modulation of CXCR1 and CXCR2, ind icating that the activation of a TK is required for LPS to mediate its effect. The effect of LPS on receptor expression paralleled the hyper phosphorylation of the protein TK p72syk, Although IL-8 induced a comp arable down-modulation of CXCR1 and CXCR2, TK inhibitors did not atten uate this effect. These studies provide the first evidence of an agoni st-independent, TK-dependent pathway of chemokine receptor regulation by endotoxin.