Interleukin-1beta inhibits PDGF-BB-induced migration by cooperating with PDGF-BB to induce cyclooxygenase-2 expression in baboon aortic smooth muscle cells.
OBJECTIVE
Smooth muscle cell (SMC) migration from the media into the intima is pivotal for intimal formation after vascular injury. Platelet-derived growth factor (PDGF)-BB is a potent chemoattractant for SMCs in vitro and in vivo. We investigated whether interleukin (IL)-1beta affects migration in response to PDGF-BB. Our data suggest that IL-1beta is inhibitory and that this effect is mediated by cyclooxygenase (COX)-2. We further addressed the role of the mitogen-activated protein kinase p38, which is activated by PDGF-BB and by IL-1beta.


METHODS
Baboon aortic SMCs were prepared with the explant method. Migration was measured in a Boyden chamber assay through filters coated with monomeric collagen. COX2 expression and phosphorylation of p38 MAPK were analyzed by Western blotting.


RESULTS
PDGF-BB (10 ng/mL) stimulates migration 3.8-fold, and IL-1beta (0.1 ng/mL) reduces this response by 40%. The inhibitory effect of IL-1beta is abolished by the COX inhibitor, indomethacin (10 micromol/L), the specific COX2 inhibitor, NS398 (10 micromol/L), and the p38 MAPK inhibitor SB203580 (3 micromol/L). We found that IL-1beta and PDGF-BB synergize to stimulate COX2 expression. We further demonstrated that p38 MAPK is activated by IL-1beta and PDGF with different kinetics and that p38 MAPK is required for maximal COX2 expression in response to IL-1beta plus PDGF-BB.


CONCLUSIONS
IL-1beta inhibits PDGF-BB-induced migration by cooperating with PDGF-BB to induce COX2 through activation of p38 MAPK. Whether this effect of IL-1beta modulates intimal growth after vascular injury remains to be elucidated.
Englesbe
Michael J
MJ
Department of Surgery, University of Washington, Seattle, Wash, USA.
Deou
Jessie
J
Bourns
Brenda D
BD
Clowes
Alexander W
AW
Daum
Günter
G
D000818:Animals; D001011:Aorta / Q000166:cytology; D000077214:Becaplermin; D015153:Blotting, Western; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010215:Papio; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins / Q000494:pharmacology; D017539:Tunica Intima / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D000077214:Becaplermin; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases