Abstract
Nonhistone chromosomal proteins of the high mobility group (HMG) affect the transcriptional regulation of certain mammalian genes. For example, HMG-I(Y) controls cytokine-mediated promoters that require transcription factors, such as nuclear factor-kappaB, for maximal expression. Even though a great deal is known about how HMG-I(Y) facilitates expression of other genes, less is known about the regulation of HMG-I(Y) itself, especially in cells in primary culture. Therefore we investigated the effect of endotoxin and the cytokine interleukin-1beta on HMG-I(Y) expression in vascular smooth muscle cells. Induction of HMG-I(Y) peaked after 48 h of interleukin-1beta stimulation (6.2-fold) in cells in primary culture, and this increase in mRNA corresponded to an increase in HMG-I(Y) protein. Moreover, immunohistochemical staining revealed a dramatic increase in HMG-I(Y) protein expression in vascular smooth muscle cells after endotoxin stimulation in vivo. This increase in HMG-I(Y) expression (both in vitro and in vivo) mirrored an up-regulation of inducible nitric oxide synthase, a cytokine-responsive gene. The functional significance of this coinduction is underscored by our finding that HMG-I(Y) potentiated the response of inducible nitric oxide synthase to nuclear factor-kappaB transactivation. Taken together, these studies suggest that induction of HMG-I(Y), and subsequent transactivation of iNOS, may contribute to a reduction in vascular tone during endotoxemia and other systemic inflammatory processes.
Highlights
Nonhistone chromosomal proteins of the high mobility group (HMG) affect the transcriptional regulation of certain mammalian genes
Even though a great deal is known about how HMG-I(Y) facilitates expression of other genes, less is known about the regulation of HMG-I(Y) itself, especially in cells in primary culture
in Vascular SMC (IL)-1 Increased HMG-I(Y) mRNA in RASMCs in Primary Culture—Because the proinflammatory cytokine IL-1 is an important downstream mediator of the vascular response to LPS, we studied the effect of IL-1 on HMG-I(Y) gene expression in vitro
Summary
Immunohistochemical staining revealed a dramatic increase in HMGI(Y) protein expression in vascular smooth muscle cells after endotoxin stimulation in vivo This increase in HMG-I(Y) expression (both in vitro and in vivo) mirrored an up-regulation of inducible nitric oxide synthase, a cytokine-responsive gene. In investigating the regulation of HMG-I(Y) in vascular smooth muscle cells in vitro and in vivo, our goals in the present study were to 1) determine whether the proinflammatory cytokine IL-1 regulated HMG-I(Y) mRNA and protein in primary cell cultures, 2) determine whether such a response occurred in smooth muscle cells of the blood vessel wall after endotoxin stimulation in vivo, 3) determine whether regulation of HMG-I(Y) correlated with induction of iNOS, and 4) determine whether HMG-I(Y) plays a role in the activation of iNOS gene transcription
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
