Identification of a novel mechanism for endotoxin-mediated down-modulation of CC chemokine receptor expression
✍ Scribed by Luoling Xu; Masud H. Khandaker; Jana Barlic; Longsi Ran; Miren L. Borja; Joaquin Madrenas; Rahbar Rahimpour; Kong Chen; Gordon Mitchell; Christopher M. Tan; Mark DeVries; Ross D. Feldman; David J. Kelvin
- Book ID
- 101380284
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 248 KB
- Volume
- 30
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
In the present study, we explored the molecular mechanisms by which bacterial endotoxin (LPS) mediates the down-regulation of CCR2 receptors on human monocytes. We found that LPS induced a marked reduction in CCR2 cell surface protein levels which was blocked by pretreatment with the tyrosine kinase inhibitors genistein and herbimycin A. The effector mechanism underlying LPS-induced CCR2 down-modulation appears to involve the enzymatic activity of proteinases since Western blot analysis of LPS-stimulated monocytes revealed the degradation of a 38-kDa species corresponding to the CCR2B monomer. In RBL cells expressing the CCR2B-green fluorescent protein (GFP) fusion chemokine receptor, LPS stimulated the internalization and degradation of CCR2. The serine proteinase inhibitor N- § -p-tosyl-L-lysine chloromethyl ketone blocked LPS-induced down-modulation of CCR2 in monocytes and CCR2B-GFP in RBL cells. This work describes a previously uncharacterized mechanism for CC chemokine receptor down-modulation that is dependent upon tyrosine kinase activation and serine proteinase-mediated receptor degradation and may provide further insight into the mechanisms of leukocyte regulation during immunological and inflammatory responses.