CXCR1 and CXCR2 are rapidly down-modulated by bacterial endotoxin through a unique agonist-independent, tyrosine kinase-dependent mechanism

Masud H. Khandaker, Luoling Xu, Rahbar Rahimpour, Gordon Mitchell, Mark E. DeVries, J. Geoffrey Pickering, Sharwan K. Singhal, Ross D. Feldman, David J. Kelvin

Research output: Contribution to journalArticlepeer-review

94 Citations (Scopus)

Abstract

The expression of the seven-transmembrane domain chemokine receptors CXCR1 and CXCR2 modulates neutrophil responsiveness to the chemoattractant IL-8 and a number of closely related CXC chemokines. In the present study, we investigated the mechanism by which bacterial LPS induces the down-modulation of IL-8 responsiveness and CXCR1 and CXCR2 expression 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-α, or IL-1β, since ELISA studies indicated that LPS-stimulated neutrophils did not release detectable amounts of these proteins before 2 h poststimulation. The tyrosine kinase (TK) inhibitors genistein and herbimycin A attenuated the LPS-mediated down-modulation of CXCR1 and CXCR2, indicating that the activation of a TK is required for LPS to mediate its effect. The effect of LPS on receptor expression paralleled the hyperphosphorylation of the protein TK p72syk. Although IL-8 induced a comparable down-modulation of CXCR1 and CXCR2, TK inhibitors did not attenuate this effect. These studies provide the first evidence of an agonist-independent, TK-dependent pathway of chemokine receptor regulation by endotoxin.

Original languageEnglish
Pages (from-to)1930-1938
Number of pages9
JournalJournal of Immunology
Volume161
Issue number4
Publication statusPublished - Aug 15 1998
Externally publishedYes

ASJC Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'CXCR1 and CXCR2 are rapidly down-modulated by bacterial endotoxin through a unique agonist-independent, tyrosine kinase-dependent mechanism'. Together they form a unique fingerprint.

Cite this