TGF-β1/ALK5-induced monocyte migration involves PI3K and p38 pathways and is not negatively affected by diabetes mellitus

• Published in: Cardiovascular research 2011-08, Vol.91 (3), p.510-518
• Main Authors: Olieslagers, Servé, Pardali, Evangelia, Tchaikovski, Vadim, ten Dijke, Peter, Waltenberger, Johannes
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; Cardiology. Vascular system; Case-Control Studies; Cells, Cultured; Chemotaxis, Leukocyte - drug effects; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - immunology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Humans; Male; Medical sciences; Middle Aged; Monocytes - drug effects; Monocytes - enzymology; Monocytes - immunology; Netherlands; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Transforming Growth Factor beta - metabolism; RNA Interference; Signal Transduction; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad3 Protein - genetics; Smad3 Protein - metabolism; Time Factors; Transfection; Transforming Growth Factor beta1 - metabolism
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvr100

Aims Monocytes contribute to arteriogenesis by infiltration to sites of collateral growth and subsequent production and release of growth factors. Transforming growth factor β1 (TGF-β1) mediates monocyte motility and stimulates arteriogenesis. TGF-β1 signalling mechanisms mediating monocyte motility are unknown so far. Moreover, the influence of cardiovascular risk factor diabetes on TGF-β1-induced monocyte migration remains to be elucidated. Methods and results Stimulation of primary human monocytes with TGF-β1 endorsed phosphorylation of v-Akt murine thymoma viral oncogene analogues protein (AKT), p38, and extracellular signal-related kinase 1/2 (ERK1/2), besides the activation of the SMA/MAD homologues protein (SMAD) pathway. Inhibition of the TGF-βtype 1 receptor, alias activin receptor-like kinase 5 (ALK5), hindered monocyte chemotaxis towards TGF-β1 and TGF-β1-activated downstream signalling cascades. Individual genetic knock-downs for receptor-regulated SMAD2 and SMAD3 did not affect monocyte migration to TGF-β1. Inhibition of phosphoinositide 3 kinase (PI3K) activity, but not AKT, diminished both basal and TGF-β1-mediated monocyte motility. TGF-β1-induced monocyte chemotaxis did not rely on ERK1/2, but rather on p38. Remarkably, TGF-β1 was able to stimulate chemotaxis of diabetic monocytes. Conclusion The current study provides novel insights into the molecular mechanisms of TGF-β1-induced monocyte migration, requiring ALK5 kinase activity and signalling via PI3K and p38. TGF-β1-driven monocyte motogenicity is fully functional in diabetic conditions, which is in sharp contrast to the impaired chemotactic responses to certain other arteriogenic cytokines. Therefore, TGF-β1 may be a promising candidate for endogenously and exogenously stimulating collateral growth in diabetic patients.