Journal
EXPERIMENTAL CELL RESEARCH
Volume 335, Issue 2, Pages 258-268Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2015.05.015
Keywords
BMDMs; IGF-1; Akt; IL-4; IFN gamma
Categories
Funding
- Science Foundation Ireland [07/IN.1/B949]
- Trinity College Postgraduate student award
- Science Foundation Ireland (SFI) [07/IN.1/B949] Funding Source: Science Foundation Ireland (SFI)
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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)gamma-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 (Chi313) and found in inflammatory zone 1 (FIZZ1) was observed. The IFN gamma-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 IFN gamma. (C) 2015 Elsevier Inc. All rights reserved.
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