Co-stimulation with IGF-1 and TLR ligands induces a pro-inflammatory response in PBMCs via activation of the MAPK pathway

Transcription

1 Co-stimulation with IGF-1 and TLR ligands induces a pro-inflammatory response in PBMCs via activation of the MAPK pathway Thalijn LC Wolters, MD 1 ; Mihai G Netea, Prof MD 2 ; Ad RMM Hermus, Prof MD 1 ; Jan WA Smit, Prof MD 1, Romana T Netea-Maier, PhD MD 1 1 Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen. 2 Department of Internal Medicine, Division of Experimental Internal Medicine, Radboud University Medical Center, Nijmegen. Abstract SAT ENDO 2017; Orlando

2 Acromegaly & Cardiovascular Diseases Acromegaly is associated with cardiovascular diseases (CVD) 1,2 Atherosclerosis Hypertension Coronary artery disease Cardiomyopathy Heart valve disease Arrhythmias Cardiac dysfunction Increased CVD risk persists after normalization of IGF-1 levels 3,4 1 Ramos-Leví & Marazuela. Endocrine Colao et al. Endocr Rev Mosca et al. Int J Cardiol Lombardi et al. J Endocrinol Invest Pagina ENDO Thalijn Wolters

3 Inflammation & CVD Pagina ENDO Thalijn Wolters Nurmohamed. Nat Rev Rheumatol. 2015

4 GH, IGF-1 & inflammation In vitro GH enhances LPS-induced monocyte-derived cytokine production in whole blood 1 In acromegaly Higher serum TNF-α & IL-8 levels compared to controls 2 Possible association between acromegaly & inflammation Neutrophil-to-lymphocyte & platelet-to-lymphocyte ratio correlate with IGF-1 levels 3 Subclinical inflammation may play a role in the increased mortality & morbidity, which depends on uncontrolled IGF-1 levels in acromegaly 1 Uronen-Hansson H et al. Growth Horm IGF Res Arikan S et al. Clin Endocrinol (Oxf) Üçler R et al. Hum Exp Toxicol Pagina ENDO Thalijn Wolters

5 GH, IGF-1 & Inflammation Hypothesis: Prolonged GH/IGF-1 excess induces activation of innate immune responses, which might contribute to cardiovascular morbidity in acromegaly Aim: To investigate the effects of GH & IGF-1 on the function of immune cells and to explore the underlying mechanisms Pagina ENDO Thalijn Wolters

6 Methods (Co) stimulation experiments PBMCs from healthy volunteers Stimuli: LPS (TLR4), Pam3Cys (TLR2), C. Albicans GH: ng/ml; IGF-1: µg/ml ELISA Pro-inflammatory Anti-inflammatory Monocyte (Mo) IL-6, TNF-α, IL-1β IL-10 T cell (Th) IFN-γ, IL-17, IL-22 (IL-10) Mechanistic studies Pagina ENDO Thalijn Wolters

7 Stimulation experiments Inflammatory cytokine production Pagina ENDO Thalijn Wolters

8 GH does not affect cytokine production Pagina ENDO Thalijn Wolters

9 IGF-1 induces cytokine production in monocytes Pagina ENDO Thalijn Wolters

10 IGF-1 induces cytokine production in T cells Pagina ENDO Thalijn Wolters

11 Mechanistic studies Pagina ENDO Thalijn Wolters

12 IGF-1 signalling: PI3K-Akt-mTOR/MAPK U0126 Rapamycin Pagina ENDO Thalijn Wolters

13 PI3K-mTor inhibitor: no effects Pagina ENDO Thalijn Wolters

14 MEK-inhibitor U0126 Reversal of IGF-1 induced cytokine production Pagina 14 U µm Inhibitor of ERK 1/2

15 Conclusions GH: no significant effects on cytokine production in PBMCs IGF-1 potentiates TLR ligand-induced inflammatory cytokine production in PBMCs; compensatory IL-10 production Involved pathway: MAPK Future perspectives To explore the effects of prolonged exposure to IGF-1 In vitro training experiments, stimulation with both GH & IGF-1 Extend these studies to acromegaly patients Pagina ENDO Thalijn Wolters

16 Acknownledgements Department of Internal Medicine Radboudumc Nijmegen Division of Endocrinology Romana Netea-Maier, MD, PhD Prof Ad Hermus, MD Prof Jan Smit, MD Division of Experimental Medicine Prof Mihai Netea, MD Division of Vascular Medicine Charlotte van der Heijden, MD Prof Niels Riksen, MD Pagina ENDO Thalijn Wolters

17 Co-stimulation with IGF-1 and TLR ligands induces a pro-inflammatory response in PBMCs via activation of the MAPK pathway Thalijn LC Wolters, MD 1 ; Mihai G Netea, Prof MD 2 ; Ad RMM Hermus, Prof MD 1 ; Jan WA Smit, Prof MD 1, Romana T Netea-Maier, PhD MD 1 1 Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen. 2 Department of Internal Medicine, Division of Experimental Internal Medicine, Radboud University Medical Center, Nijmegen. Abstract SAT ENDO 2017; Orlando