Abstract


Introduction: Patients with acromegaly have an increased risk to develop cardiovascular disease (CVD). Recent data demonstrate a crucial role of innate immune responses in the development of CVD. In addition, a regulatory role of IGF-1 in the development of subclinical inflammation via inflammatory activation of peripheral monocytes has been suggested. We hypothesize that supra-physiological levels of Growth Hormone (GH) and/or Insulin-like Growth Factor-1 (IGF-1) induce a pro-inflammatory state via circulating immune cells, which contributes to an increased CVD risk. view more

Introduction: Patients with acromegaly have an increased risk to develop cardiovascular disease (CVD). Recent data demonstrate a crucial role of innate immune responses in the development of CVD. In addition, a regulatory role of IGF-1 in the development of subclinical inflammation via inflammatory activation of peripheral monocytes has been suggested. We hypothesize that supra-physiological levels of Growth Hormone (GH) and/or Insulin-like Growth Factor-1 (IGF-1) induce a pro-inflammatory state via circulating immune cells, which contributes to an increased CVD risk. The aim of this study was to assess the effect of GH/IGF-1 on cytokine production induced by various Toll-like receptors (TLR) ligands. 
Methods: PBMCs (peripheral blood mononuclear cells) were obtained from healthy volunteers and were stimulated with Toll-like receptor (TLR) ligands (LPS, Pam3Cys, C. Albicans) and different concentrations of GH & IGF-1. Levels of pro-inflammatory (TNF-α, IL-6, IL-1β, IFN-γ, IL-17, IL-22) and anti-inflammatory (IL-10) cytokines were measured. The underlying signaling pathways were investigated by targeted inhibition of PI3K-mTOR and MAPK pathways, which are known downstream targets of the IGF-1 receptor.
Results: Direct stimulation of PBMCs with various concentrations of GH and IGF-1 alone did not influence inflammatory cytokine production. Neither did GH affect TLR-induced cytokine production. In contrast, co-stimulation with IGF-1 increased the LPS- and the Pam3Cys-induced IL-6 production (P<0.01), LPS-induced TNF-α production (P= 0.016), but also C.Albicans-induced IFN-γ production (P= 0.002) and TLR-induced anti-inflammatory IL-10 production (P=0.01). These effects were dose-dependent. In contrast, IGF-1 had no effects on IL-1β, IL-17 and IL-22 production. Blocking the mTOR pathway with Rapamycin did not reduce TNF-α or IL-6 production after stimulation with both IGF-1 and LPS. However, the MEK-inhibitor U0126 significantly reduced production of TNF-α and IL-6 (P=0.016 resp. P=0.008) after co-stimulation with IGF-1 and LPS; in addition, we observed reduced expression of phosphorylated ERK. 
Conclusions: IGF-1, but not GH, has pro-inflammatory effects; the MAPK signaling pathway is involved. This mechanism might be involved in the pathogenesis of atherosclerosis in acromegaly. The increased IL-10 production possibly counteracts the pro-inflammatory effects.

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