The selective CXCR2 antagonist SB272844 blocks interleukin-8 and growth-related oncogene-alpha-mediated inhibition of spontaneous neutrophil apoptosis.
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.
Glynn
P C
PC
Division of Therapeutics, University of Nottingham South Block, C Floor, Queens Medical Centre, Nottingham, NG7 2UH.
Henney
E
E
Hall
I P
IP
D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects*; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*
D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B