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 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-alpha, or IL-1beta, 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.
Department of Microbiology and Immunology, University of Western Ontario, London, Canada.
M H
MH
Khandaker
L
L
Xu
R
R
Rahimpour
G
G
Mitchell
M E
ME
DeVries
J G
JG
Pickering
S K
SK
Singhal
R D
RD
Feldman
D J
DJ
Kelvin
D015703:Antigens, CD / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D016227:Benzoquinones; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008970:Molecular Weight; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000819:agonists / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000072377:Syk Kinase; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D007375:Interleukin-1; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; D011809:Quinones; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019204:GTP-Binding Proteins