Estrogen modulates TNF-α-induced inflammatory responses in rat aortic smooth muscle cells through estrogen receptor-β activation

We have previously shown that 17β-estradiol (E2) attenuates responses to endoluminal injury of the rat carotid artery, at least in part, by decreasing inflammatory mediator expression and neutrophil infiltration into the injured vessel, with a major effect on the neutrophil-specific chemokine cytokine-induced neutrophil chemoattractant (CINC)-2β. Current studies tested the hypothesis that activated rat aortic smooth muscle cells (RASMCs) express these same inflammatory mediators and induce neutrophil migration in vitro and that E2 inhibits these processes by an estrogen receptor (ER)-dependent mechanism. Quiescent RASMCs treated with E2, the ERα-selective agonist propyl pyrazole triol (PPT), the ERβ-selective agonist diarylpropiolnitrile (DPN), or vehicle for 24 h were stimulated with tumor necrosis factor (TNF)-α and processed for real-time RT-PCR, ELISA, or chemotaxis assays 6 h later. TNF-α stimulated and E2 attenuated mRNA expression of inflammatory mediators, including P-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, monocyte chemoattractant protein (MCP)-1, and CINC-2β. DPN dose dependently attenuated TNF-α-induced mRNA expression of CINC-2β, whereas PPT had no effect. The anti-inflammatory effects of DPN and E2 were blocked by the nonselective ER-inhibitor ICI-182,780. ELISA confirmed the TNF-α-induced increase and E2-induced inhibition of CINC-2β protein secretion. TNF-α treatment of RASMCs produced a twofold increase in neutrophil chemotactic activity of conditioned media; E2 and DPN treatment markedly inhibited this effect. E2 inhibits activated RASMC proinflammatory mediator expression and neutrophil chemotactic activity through an ERβ-dependent mechanism.

Gc-Globulin: Roles in Response to Injury

Background: Gc-globulin (vitamin D–binding protein) appears to have important functions in addition to its role as a carrier of vitamin D. Approach: We reviewed recent studies focusing on the pathophysiologic functions and clinical significance of Gc-globulin. Results: Serum concentrations of Gc-globulin, as determined by immunoassay techniques, are decreased in severe injury. The extent of the decrease may have prognostic significance for patient outcomes. Clinical studies and animal models have shown that Gc-globulin has an important role in the clearance of procoagulant actin from the circulation after its release during cell necrosis and tissue injury. Gc-globulin has other potential roles in responses to acute tissue injury through conversion to a macrophage-activating factor, neutrophil chemotactic activity, and enhancement of C5a-mediated signaling. Conclusion: Considering the important physiologic roles of Gc-globulin in responses to tissue injury, such as clearance of actin, measurement of Gc-globulin may have value in directing the care of patients in many clinical disorders.