Regulation of CD44 gene expression by the proinflammatory cytokine interleukin-1beta in vascular smooth muscle cells.
The CD44 gene codes for a family of alternatively spliced, multifunctional adhesion molecules that participate in extracellular matrix binding, lymphocyte activation, cell migration, and tumor metastasis. In a mouse model of transplant-associated arteriosclerosis, CD44 protein was induced in the neointima of allografted vessels and colocalized with a subset of proliferating vascular smooth muscle cells (SMC). To elucidate the molecular mechanisms regulating CD44 expression in this model, we investigated the regulation of CD44 gene expression by interleukin (IL)-1beta. Treatment of rat aortic SMC with IL-1beta resulted in a 5.3-fold increase in cell surface CD44 expression. Northern analysis showed that IL-1beta promoted a dose- and time-dependent induction of CD44 mRNA which reached 6.6-fold after 48 h, and nuclear run-on analysis showed that IL-1beta increased the rate of CD44 gene transcription within 8 h of stimulation. In transient reporter gene transfection experiments in rat aortic SMC, a 1.4-kilobase fragment of the mouse CD44 5'-flanking sequence mediated this response to IL-1beta. Regulation of CD44 gene expression by the proinflammatory cytokine IL-1beta may contribute to SMC phenotypic modulation in the pathogenesis of arteriosclerosis.
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
L C
LC
Foster
B M
BM
Arkonac
N E
NE
Sibinga
C
C
Shi
M A
MA
Perrella
E
E
Haber
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000502:physiology; D001161:Arteriosclerosis / Q000503:physiopathology; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D018960:Hyaluronan Receptors / Q000235:genetics*; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017422:Sequence Analysis, DNA; D014184:Transplantation, Homologous / Q000276:immunology
D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; D007375:Interleukin-1; D012333:RNA, Messenger