title: TLR-induced activation of neutrophils promotes histamine production via a PI3 kinase dependent mechanism.
abstract: Histamine is a bioactive amine that exerts immunomodulatory functions, including many allergic symptoms. It is preformed and stored in mast cells and basophils but recent evidence suggests that other cell types produce histamine in an inducible fashion. During infection, it has been suggested that neutrophils may produce histamine. We also observed that histamine is released in a neutrophil-mediated LPS-induced model of acute lung injury. Therefore, we sought to examine whether innate signals promote histamine production by neutrophils. Bone marrow-derived neutrophils stimulated with a range of TLR agonists secreted histamine in response to LPS or R837, suggesting TLR4 or TLR7 are important. LPS-driven histamine was enhanced by coculture with GM-CSF and led to a transient release of histamine that peaked at 8h post stimulation. This was dependent upon de novo synthesis of histamine, since cells derived from histidine decarboxylase (HDC) deficient mice were unable to produce histamine but did generate reactive oxygen species upon stimulation. Using pharmacological inhibitors, we show that histamine production requires PI3 kinase, which has been shown to regulate other neutrophil functions, including activation and selective granule release. However, unlike mast cells, HDC deficiency did not alter the granule structure of neutrophils, suggesting that histamine does not participate in granule integrity in these cells. Consequently, our findings establish that neutrophils generate histamine in response to a select panel of innate immune triggers and that this might contribute to acute lung injury responses.
authors: Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Craig
authors: C
authors: Smuda
authors: Joshua B
authors: JB
authors: Wechsler
authors: Paul J
authors: PJ
authors: Bryce
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001491:Basophils / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006632:Histamine / Q000096:biosynthesis; D006640:Histidine Decarboxylase / Q000172:deficiency / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D011804:Quinolines / Q000008:administration & dosage; D015398:Signal Transduction / Q000502:physiology
chemical_list: C557465:1-(2-methylpropyl)-1H-imidazo(4,5-c)quinolin 4-amine; D008070:Lipopolysaccharides; D011804:Quinolines; D006632:Histamine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D058539:Phosphatidylinositol 3-Kinase; D006640:Histidine Decarboxylase