Growth factor and cytokine-regulated hyaluronan-binding protein TSG-6 is localized to the injury-induced rat neointima and confers enhanced growth in vascular smooth muscle cells.
Hyaluronan (HA) and HA-binding proteins have been implicated in a diverse array of biological processes, including development, tissue repair, and tumor invasion. However, the role of HA and HA-binding proteins in atherosclerosis and restenosis is poorly understood. PS4 (TSG-6) is a HA-binding protein expressed by cultured vascular smooth muscle cells (SMCs) in response to serum and growth factor stimulation. To delineate a possible role for TSG-6 in vascular disease progression, we have characterized its expression in cultured SMCs and in a rat vascular injury model, and we have studied the effect of constitutive overexpression of TSG-6 on SMC behavior. We found that interleukin-1 (IL-1) but not tumor necrosis factor or interleukin-6 was able to stimulate TSG-6 expression in SMCs. The IL-1 pathway could be distinguished from the growth factor pathway by its insensitivity to protein synthesis inhibitors. Furthermore, epidermal growth factor, fibroblast growth factor-1, and transforming growth factor-beta1 were all capable of augmenting maximum IL-1-induced expression of TSG-6. To gain further insight into the function of TSG-6 in SMCs, we examined the effect of constitutive overexpression of TSG-6 on these cells. We found that TSG-6-overexpressing cells grew >50% faster than control cells. Furthermore, this growth advantage became more evident in the absence of serum growth factors, with an average increase in cell number of 118% over control cells after 6 days. Consistent with these in vitro data, we observed intense immunostaining for TSG-6 in proliferating SMCs in the rat neointima after injury, whereas only an occasional cell was positive for TSG-6 in the medial layer and in nonballooned arteries. We conclude that the expression of TSG-6 is tightly controlled by growth factors and cytokines via two distinct pathways in SMCs and that overexpression of TSG-6 confers a growth advantage to these cells.
Ye
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Department of Molecular Biology, Jerome H. Holland Laboratory, American Red Cross, Rockville, Md 20855, USA.
Mora
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R
Akhayani
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Haudenschild
C C
CC
Liau
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G
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology*; D006820:Hyaluronic Acid / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000293:injuries* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D016207:Cytokines; D006133:Growth Substances; D007375:Interleukin-1; D012333:RNA, Messenger; C513056:Tnfaip6 protein, rat; D016212:Transforming Growth Factor beta; D016220:Fibroblast Growth Factor 1; D004815:Epidermal Growth Factor; D006820:Hyaluronic Acid