PDGF enhancement of IL-1 receptor levels in smooth muscle cells involves induction of an attachment-regulated, heparan sulfate binding site (IL-1RIII)

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Abstract

This study shows that increase in IL-1 receptor levels by platelet derived growth factor (PDGF) involves an enhancement of a matrix-dependent, low-affinity receptor that constitutes a heparan sulfate. Fibronectin attachment caused pronounced alterations in IL-1 receptor function in smooth muscle cells, involving a pronounced increase in cell surface binding from an average of 2,000 up to approximately 8,000 receptors/cell and an increase in affinity (Ka) of the type I receptor from 1.8 ± 0.9 × 109 to 3.7 ± 0.5 × 109 M-1. PDGF stimulation similarly enhanced the level of cell surface binding by between 30% and 100%, with, in general, less effect on cells plated on fibronectin. Further, PDGF had a pronounced effect on the type I receptor affinity in the absence of matrix attachment, increasing the Ka from 1.77 ± 0.93 × 109 to 5.1 ± 2.1 × 109 M-1. Scatchard analyses revealed that PDGF, similarly to fibronectin attachment, caused enhancement of a second low-affinity binding site. Antibody blocking showed that approximately 50% of the attachment-induced increase was independent of type I receptor binding. Further, a similar fraction of the cell surface interaction was blocked by soluble heparan sulfate and dependent on cell binding to the heparan binding site. Cross-linking demonstrated that, in addition to the type I receptor, IL-1 bound to a second high molecular weight complex of 300 kd, induced by fibronectin attachment as well as by PDGF in the absence of matrix. Biochemical analyses demonstrated that this second site constitutes a heparan sulfate, which directly interacted with the type I receptor after recruitment to the complex, and which bound up to 50% and 25% of the ligand after fibronectin attachment and PDGF stimulation, respectively. The data show that PDGF induces an attachment-regulated low-affinity IL-1 binding site in smooth muscle cells, constituting a heparan sulfate. Correlation of the recruitment of this component to the IL-1 receptor complex with structural regulation of receptor function and enhancement of IL-1-mediated responses suggests that this is a significant mechanism in PDGF augmentation of local inflammatory responses during vessel wall pathogenesis.

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Valles, S., Caunt, C. J., Walker, M. H., & Qwarnstrom, E. E. (2002). PDGF enhancement of IL-1 receptor levels in smooth muscle cells involves induction of an attachment-regulated, heparan sulfate binding site (IL-1RIII). Laboratory Investigation, 82(7), 855–862. https://doi.org/10.1097/01.LAB.0000020420.07575.3F

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