title: Involvement of IGF-1 and Akt in M1/M2 activation state in bone marrow-derived macrophages.
abstract: Macrophages can be polarised to adopt the M1 or M2 phenotype and functional outcomes of activation include altered secretion of immune molecules such as insulin-like growth factor (IGF)-1 as well as upregulation of cell surface molecules specifically associated with each state. Interleukin (IL)-4 mediates its effects through two receptors, the type I and II receptors and activation of these receptors results in phosphorylation of signal transducers and activators of transcription (STAT)6. JAK3 is activated as a consequence of ligation of the type I IL-4R, which participates in Akt activation. We set out to investigate the impact of perturbation of IGF-1 tone on IL-4- and interferon (IFN)γ-induced activation, the mechanisms by which this may occur and the contribution of type I IL-4R activation to adoption of the M2 state. The data presented here indicate that IL-4-induced activation of Akt is JAK3-dependent, enhanced by release of IGF-1 and necessary for full adoption of the M2 phenotype, since blocking IGF-1 activity blunts the ability of IL-4 to induce activation of Akt and to upregulate expression of some M2-associated molecules. In addition, differential control of the expression of mannose receptor (MRC1), arginase-1 (Arg-1), chitinase-3 like 3 (Chi3l3) and found in inflammatory zone 1 (FIZZ1) was observed. The IFNγ-induced decrease in IGF-1 was exacerbated by inhibition of phosphatidylinositol-3 (PI3) kinase, indicating that Akt may regulate its own activation via IGF-1. Overall, a deficit in IGF-1/Akt signalling is associated with decreased capacity to induce the M2 state and an increased responsiveness to IFNγ.
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: James P
authors.initials: JP
authors.lastname: Barrett
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. Electronic address: aminogu@tcd.ie.
authors.forename: Aedín M
authors.initials: AM
authors.lastname: Minogue
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Aidan
authors.initials: A
authors.lastname: Falvey
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Lynch
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D053616:Janus Kinase 3 / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D015847:Interleukin-4; D007334:Insulin-Like Growth Factor I; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt;; BMDMs;; IFNγ;; IGF-1;; IL-4;