Systemic administration of interleukin-2 inhibits inflammatory neutrophil migration: role of nitric oxide.
1. Interleukin-2 (IL-2) has proinflammatory properties that limit its therapeutic use. Its side effects are mainly explained by the induction of a vascular leakage syndrome. Cytokines, as TNF-alpha and IL-1beta, and nitric oxide (NO) generated by IL-2-activated leukocytes play a role in this defect. 2. As the systemic release of these mediators inhibits neutrophil migration to a specific inflammatory site, we investigated now whether IL-2 administrated systemically inhibits the neutrophil recruitment to the inflamed peritoneum. The involvement of NO in the process was also addressed. 3. Using peritoneal neutrophils, we show that the intravenous treatment of the mice with IL-2 inhibits the neutrophil migration induced by carrageenin, LPS or fMLP. In confirmation, IL-2-treated mice showed a significant reduction in leukocyte rolling and adhesion in mesenteric microcirculation evaluated after carrageenin, LPS and fMLP injections. Aminoguanidine prevented the inhibitory effect of IL-2 on carrageenin-induced neutrophil migration, rolling and adhesion. In contrast, IL-2 failed to reduce the lung leukocyte infiltration induced by LPS. Therefore, IL-2 inhibition of neutrophil migration is organ specific. 4. Our results indicate that IL-2 administered systemically inhibits neutrophil recruitment to some inflammatory sites through a mechanism dependent on NO. The results also reinforce the needs to determine the mechanism by which patients treated with IL-2 show increased risks of infection.
Moreno
Susana E
SE
1Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Alves-Filho
José C
JC
Bertozi
Giuliana
G
Alfaya
Tais M
TM
Thèze
Jacques
J
Ferreira
Sergio H
SH
Vargaftig
Bernardo Boris
BB
D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D007249:Inflammation / Q000473:pathology; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000096:biosynthesis
D007376:Interleukin-2; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002351:Carrageenan