IGF-1 increases macrophage motility via PKC/p38-dependent alphavbeta3-integrin inside-out signaling.
Macrophage migration is a key aspect in the initiation and progression of atherosclerosis. Insulin-like growth factor (IGF)-1 is highly expressed in macrophages in human atheroma. Its function in macrophage motility, however, remains to be elucidated. The aim of this study was to investigate the impact of IGF-1 on macrophage migration, its signaling pathways and the involvement of integrins and/or matrix metalloproteinases (MMPs).


RESULTS
Migration checker-box experiments demonstrated that IGF-1 induced chemotaxis in human THP-1/macrophages. IGF-1 induced migration was inhibited by RGD-containing peptides and the alphavbeta3-blocking antibody LM609, but was unaffected by the MMP-inhibitor GM6001. Immunoblotting demonstrated that IGF-1 did not affect the activation of MMPs or TIMPs, nor did it increase alphav-integrin protein levels. However, IGF-1 induced recruitment of alphavbeta3, as well as trans-location of the integrin adaptor protein phospho-paxillin to focal adhesion sites. Pharmacological blocking experiments with specific inhibitors of Akt, PKC and p38 MAP-kinase revealed that IGF-1-dependent activation of focal adhesion kinase (FAK) and paxillin, and consecutively IGF-1 facilitated migration, required IGF-1/IGF-1R-mediated PI3-kinase/PKC/p38-dependent integrin inside-out signaling.


CONCLUSIONS
IGF-1 plays a vital role in macrophage migration critically implicated in tissue inflammation. This involves activation of integrins and focal adhesion formation via inside-out PI3-kinase/PKC/p38-dependent signaling, but does not require MMP activation.
Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
Vesna
V
Furundzija
Jan
J
Fritzsche
Jan
J
Kaufmann
Heike
H
Meyborg
Eckart
E
Fleck
Kai
K
Kappert
Philipp
P
Stawowy
D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D039302:Integrin alphaVbeta3; D007334:Insulin-Like Growth Factor I; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases