title: Regulation of activin A release from murine bone marrow-derived neutrophil precursors by tumour necrosis factor-α and insulin.
abstract: Activin A, a transforming growth factor-β family cytokine, plays a crucial role in regulating the onset and severity of many inflammatory conditions, such as acute lipopolysaccharide (LPS)-induced inflammation. Activin A is also implicated in type 2 diabetes (T2D), a disease characterised by insulin resistance, hyperglycaemia and chronic elevation of pro-inflammatory cytokines, including tumour necrosis factor (TNF-α). In the human, neutrophils contain activin A that can be released in response to TNF-α. Studies of inflammatory disease in vivo, however, generally use the mouse, so it is essential to know if murine neutrophils have similar properties. Regulation of activin A was investigated in bone marrow-derived neutrophil precursors (BMNPs) from 8 to 10 weeks old C57BL6/J male mice. The BMNPs contained 7-fold higher concentrations of activin A than bone marrow mononuclear cells. Release of activin A from isolated BMNPs was stimulated by TNF-α, but this was not due to increased activin A production. In contrast to TNF-α, LPS had no effect on isolated BMNPs, but stimulated activin A release and production in total bone marrow cell cultures. Moreover, activin A release in response to LPS, was not prevented in TNF-α null mice. Increased glucose and insulin had no effect on base-line activin A secretion by BMNPs in culture, but pre-treatment with insulin blocked the TNF-α induced release of activin A. These results indicate that murine neutrophils are a source of stored activin A, the release of which can be directly stimulated by TNF-α, although TNF-α is not the only stimulator of activin A release during inflammation. Furthermore, regulation of neutrophil activin A release by insulin may also play a role in the inflammation associated with T2D.
authors.affiliation: Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia. hui.wu@monash.edu
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Winnall
authors.forename: David J
authors.initials: DJ
authors.lastname: Phillips
authors.forename: Mark P
authors.initials: MP
authors.lastname: Hedger
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology; D007249:Inflammation; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; C422405:activin A; D028341:Activins; D005947:Glucose