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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Dermatologi och venereologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Dermatology and Venereal Diseases (hsv//eng)

Nyckelord

Administration

Intranasal

Animals

Antibodies

Monoclonal/administration & dosage

Bronchoalveolar Lavage Fluid/cytology/immunology

Dose-Response Relationship

Immunologic

Inflammation/blood/immunology

inhibitors/immunology/*physiology

Injections

Intraperitoneal

Interleukin-17/analysis/antagonists & inhibitors/immunology/*physiology

Interleukin-6/antagonists & inhibitors/metabolism/secretion

Lipopolysaccharides/*administration & dosage

Lung/*immunology/pathology

Male

Mice

Mice

Inbred C57BL

Monokines/antagonists & inhibitors/metabolism/secretion

Neutrophil Infiltration/*immunology

Neutrophils/immunology/metabolism/pathology/secretion

Solubility

T-Lymphocytes/immunology/metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)