The selective CXCR2 antagonist SB272844 blocks interleukin-8 and growth-related oncogene-alpha-mediated inhibition of spontaneous neutrophil apoptosis

Pulm Pharmacol Ther. 2002;15(2):103-10. doi: 10.1006/pupt.2001.0323.

Abstract

The aims of this study were to investigate the effects of Interleukin-8 (IL-8) and Growth related oncogene-alpha (Gro-alpha) on neutrophil apoptosis and determine the potential for a selective CXCR2 antagonist to inhibit these responses. IL-8 and Gro-alpha both produced dose dependent inhibition of spontaneous human neutrophil apoptosis after 16 hours incubation (59+/-3.5% and 27.5+/-3% respectively; EC50s 2.2+/-1.8 nM, and 0.5+/-0.2 nM respectively). The pro-survival effect of a fixed concentration of agonist (IL-8 or Gro-alpha) on cultured neutrophils was abrogated by a selective CXCR2 antagonist SB272844 (K(D)s 253 nM and 49.9 nM in the presence of IL-8 or Gro-alpha respectively). Our data suggests that the anti-apoptotic effect of Gro-alpha is mediated through CXCR2 as selective CXCR2 blockade with SB272844 can potently abrogate this response. The inhibitory effect of IL-8 may in addition partly be mediated through CXCR1 as SB272844 was less potent in its ability to abrogate the anti-apoptotic effects of IL-8 when this agent was used as an agonist. CXCR2 antagonists may have a therapeutic role in controlling neutrophil-driven inflammation by reducing neutrophil recruitment and restoring neutrophils to the tissue clearance pathway of apoptosis.

MeSH terms

  • Apoptosis / drug effects*
  • Cells, Cultured
  • Humans
  • Interleukin-8 / physiology*
  • Neutrophils / drug effects*
  • Receptors, Interleukin-8A / antagonists & inhibitors*
  • Receptors, Interleukin-8B / antagonists & inhibitors*

Substances

  • Interleukin-8
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B