title: TGF-β1/ALK5-induced monocyte migration involves PI3K and p38 pathways and is not negatively affected by diabetes mellitus.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology and the Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
authors.forename: Servé
authors.initials: S
authors.lastname: Olieslagers
authors.forename: Evangelia
authors.initials: E
authors.lastname: Pardali
authors.forename: Vadim
authors.initials: V
authors.lastname: Tchaikovski
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D009426:Netherlands; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse