A Ca2+-dependent autoregulation of lipopolysaccharide-induced IL-8 receptor expression in human polymorphonuclear neutrophils.
IL-8, a potent neutrophil chemotactic agent, is known to be a key mediator in several inflammatory diseases. We found that 10 ng/ml of serum-activated LPS (Escherichia coli) efficiently up-regulated IL-8R on the surface of neutrophils within 30 min of LPS stimulation by 115 to 120% through de novo protein synthesis. After 30 min of LPS stimulation, reduction of IL-8R level was initiated and the normal level was restored within 2 h of LPS interaction. EDTA or EGTA and bestatin separately inhibited the receptor down-regulation by 98%, indicating the involvement of metalloprotease(s), more specifically an aminopeptidase in the process. Induction and subsequent reduction of IL-8 binding in serum- activated LPS-stimulated cells have been demonstrated in autoradiography. Intracellular Ca2+ level in these stimulated neutrophils was increased and decreased with alteration of IL-8R level. Although IL-8 binding was drastically reduced, the total IL-8R level, as detected by anti-IL-8R Ab measured by 125I-labeled anti-rabbit IgG, remained almost unaltered, indicating that minimal proteolysis occurred in IL-8R. Anti-IL-8R Ab and IL-8 itself could prevent this down-regulation significantly, suggesting that the susceptible epitope(s) might be in the IL-8 binding domain of the receptor. Under Ca2+-depleted conditions, the proteolysis was inhibited, which was accelerated upon addition of 1 mM of CaCl2. The study demonstrates that LPS- induced up-regulation of IL-8R leads to amplified IL-8-mediated biologic responses of neutrophils that are restored to normal level by activation of a Ca2+-dependent aminopeptidase. This may be useful for understanding the regulation of LPS-mediated inflammatory responses of neutrophils during bacterial infection.[1]References
- A Ca2+-dependent autoregulation of lipopolysaccharide-induced IL-8 receptor expression in human polymorphonuclear neutrophils. Bhattacharya, C., Samanta, S., Gupta, S., Samanta, A.K. J. Immunol. (1997) [Pubmed]
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