Endogenous IL-17 as a mediator of neutrophil recruitment caused by endotoxin exposure in mouse airways.
We have previously demonstrated that administration of the recently described cytokine IL-17 in rat airways in vivo recruits and activates neutrophils locally. In the current study, we examined whether endogenous IL-17 is involved in mediating neutrophil recruitment caused by endotoxin exposure in mouse airways. Our in vivo data show that local endotoxin exposure causes the release of free, soluble IL-17 protein 6 h later. Systemic pretreatment with a neutralizing anti-IL-17 Ab almost completely inhibits neutrophil recruitment 24 h, but not 6 h, after endotoxin exposure in the airways. Pretreatment with neutralizing anti-IL-6 and anti-macrophage inflammatory protein (MIP)-2 Abs inhibits neutrophil recruitment caused by local endotoxin exposure and IL-17, respectively. Our in vitro data show that endotoxin exposure stimulates the release of soluble IL-17 protein in T lymphocytes harvested from lung and spleen, respectively, and that this cytokine release requires coculture with airway macrophages. Intracellular IL-17 protein is detected in T lymphocytes from spleen but not in airway macrophages after coculture and stimulation of these two cell types. Finally, anti-IL-17 does not alter endotoxin-induced release of IL-6 and MIP-2 from T lymphocytes and airway macrophages in coculture. In conclusion, our results indicate that endotoxin exposure causes the release of IL-17 from T lymphocytes and that this cytokine release requires the presence of macrophages. Once released, endogenous IL-17 acts in part by inducing local release of neutrophil-mobilizing cytokines such as IL-6 and MIP-2, from nonlymphocyte, nonmacrophage cells, and this contributes to recruitment of neutrophils in the airways. These IL-17-related mechanisms constitute potential targets for pharmacotherapy against exaggerated neutrophil recruitment in airway disease.
Miyamoto
Masahide
M
Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Institute of Internal Medicine, Göteborg University, Gothenburg, Sweden.
Prause
Olof
O
Sjöstrand
Margareta
M
Laan
Martti
M
Lötvall
Jan
J
Lindén
Anders
A
D000281:Administration, Intranasal; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D054426:Chemokine CXCL2; D004306:Dose-Response Relationship, Immunologic; D007249:Inflammation / Q000097:blood / Q000276:immunology; D018836:Inflammation Mediators / Q000032:analysis / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D007274:Injections, Intraperitoneal; D020381:Interleukin-17 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015846:Monokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D054426:Chemokine CXCL2; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; D008070:Lipopolysaccharides; D015846:Monokines; D000093242:Interleukin-6 Inhibitors